Oxidative Medicine and Cellular Longevity

Oxidative Medicine and Cellular Longevity / 2015 / Article

Review Article | Open Access

Volume 2015 |Article ID 481782 | 11 pages | https://doi.org/10.1155/2015/481782

Cellular Mechanisms of Oxidative Stress and Action in Melanoma

Academic Editor: David Pattison
Received22 Dec 2014
Accepted21 Apr 2015
Published06 May 2015


Most melanomas occur on the skin, but a small percentage of these life-threatening cancers affect other parts of the body, such as the eye and mucous membranes, including the mouth. Given that most melanomas are caused by ultraviolet radiation (UV) exposure, close attention has been paid to the impact of oxidative stress on these tumors. The possibility that key epigenetic enzymes cannot act on a DNA altered by oxidative stress has opened new perspectives. Therefore, much attention has been paid to the alteration of DNA methylation by oxidative stress. We review the current evidence about (i) the role of oxidative stress in melanoma initiation and progression; (ii) the mechanisms by which ROS influence the DNA methylation pattern of transformed melanocytes; (iii) the transformative potential of oxidative stress-induced changes in global and/or local gene methylation and expression; (iv) the employment of this epimutation as a biomarker for melanoma diagnosis, prognosis, and drug resistance evaluation; (v) the impact of this new knowledge in clinical practice for melanoma treatment.

1. Introduction

Reactive oxygen species (ROS), including superoxide (), hydrogen peroxide (H2O2), and the hydroxyl radical (OH), are produced not only by specialised phagocytic cells, but also during normal oxidative metabolism and proliferative processes. The intracellular reduction of ROS is physiologically catalyzed by superoxide dismutase, catalase, and glutathione peroxidase (GPx) [1]. Superoxide dismutases (i.e., SOD1 and SOD2) catalyze the dismutation of the superoxide anion () to H2O2 [2, 3]. H2O2 in turn is decomposed into H2O and O2 by catalase [1], while GPx reduces lipid hydroperoxides to their corresponding alcohols and free hydrogen peroxide to water by employing glutathione (GSH) as its oxidation substrate [3].

H2O2 can even mimic the G1 to S phase transition induced by the exposure to growth factors [4, 5]. Moreover, low ROS levels may behave as second messengers of signal transduction pathways involved in cell growth, transformation, and apoptosis [6]. There are many discrepancies about the role that ROS have in the regulation of cell proliferation and the mechanisms leading to their formation. While high levels of ROS can cause cellular oxidative stress and induce apoptosis, low levels of superoxide and H2O2 can promote G1 → S cell cycle transition in various cell systems [4]. Indeed, high concentrations of H2O2 activate cell death through the activation of peroxidation reactions and come into equilibrium with Bcl2, an antiapoptotic member of Bcl family, which exerts antioxidant activity [7]. Such activity of Bcl2 is enhanced by several protein kinases activated by oxidative stress, including MAPKs, ERK1/2, and the JNK1 [8, 9]. The resulting phosphorylation of Bcl2 stimulates its antioxidant function in an attempt to block the apoptosis response. Moreover, it was found that H2O2 not only activates MAPK (ERK1/2) and Cdk2 but also can specifically downregulate p27, a significant inhibitor of Cdk2 and G1 → S cell cycle progression [10, 11], thus indicating a mechanism by which H2O2 can stimulate cell proliferation [12]. However, H2O2 is also able to regulate the cellular localization of p27Kip1 in transformed melanocytes, since melanoma cells overexpressing or treated with exogenous catalase exhibit a high percentage of p27Kip1 positive nuclei, as compared with melanoma cells deficient in catalase. The addition of H2O2 (0.1 µM) to melanoma cells arrested in G1 by serum starvation induces proliferation and the cytoplasmic localization of p27Kip1. Therefore, it has been concluded that H2O2 scavenging prevents nuclear exportation of p27Kip1, allowing cell cycle arrest, and it has been suggested that cancer cells take advantage of their intrinsic prooxidant state to favour cytoplasmic localization of p27Kip1 [13]. The critical role of ROS levels in the progression from G1 → S phase is underlined by the observation that cells treated with the antioxidants or deprived of growth factors exhibit very low levels of ROS and remain quiescent [12]. These data show a strong relationship between ROS levels and cell cycle status.

2. Oxidative Imbalance and Human Diseases

Although cellular stress responses, such as the heat shock, unfolded protein, DNA damage, and oxidative stress, are an integral part of normal physiology to either ensure the cell’s survival or alternatively eliminate damaged or unwanted cells, depending on a set of different factors, aberrant cellular stress responses are tightly linked to many common human diseases. Among these, it seems that diabetes is particularly sensitive to oxidative stresses. In type 1 diabetes the autoimmune response leads to the production of proinflammatory cytokines, which induce the apoptosis of β-cells by generating and ROS through the activation of NF-κB [14, 15]. The role of the oxidative stress in the pathogenesis of type 2 diabetes is less defined. The most likely hypothesis, involving the endoplasmic reticulum stress induced by glucolipotoxicity [16], is the inability of the β-cells to secrete insulin. Several evidences are provided about a significant role of ROS generation and the stress response in neurodegenerative disorders, such as Parkinson’s disease, in which they seem to be responsible for the loss of dopaminergic neurons [17, 18]. Moreover, a strong connection between oxidative stress and the formation of amyloid deposits has been demonstrated in other neurodegenerative disorders [1922], indicating the important role for protein misfolding, aggregation, and formation of protein inclusions in these chronic diseases, such as Alzheimer’s disease and Huntington’s disease [23]. That there is a short circuit between the formation of amyloid deposits and oxidative stress has been long demonstrated in a variety of cell lines where  β-amyloid deposition caused activation of NADPH oxidase (NOX) and release of ROS [24, 25]. Strong heat shock response and Unfolded Protein Response (UPR) have been associated with myocardial infarction, and, furthermore, generation of ROS has been held responsible for mitochondrial damage [26] and apoptosis in cardiac myocytes [27]. Generation of reactive oxygen species has been shown to be heavily implicated in age-related macular degeneration (ARMD). In such a disease, oxidative imbalance and DNA damage are widened by chronic smoke and alcohol consumption. Therefore, these behavioral habits have been considered an aggravating factor for ARMD because of their ability to exacerbate the oxidative stress [28, 29].

3. Association between Oxidative Stress and Aberrant Proliferation

Increased expression of the protooncogene Bcl2 or functionally activated Bcl2 can enhance SOD, catalase, and GPx activities leading to decreased levels of ROS, retardation of G1→ S cell cycle transition, and reduced cell proliferation [3, 12, 30]. These data may lead one to deduce that braking ROS formation allows the cell to engage DNA repair processes to ensure survival, in view of increased ROS levels which may contribute to genomic instability that is a hallmark of cancer cells [12]. Indeed, although superoxide anion and other ROS have been associated for many years with oncogenesis, only recently a new role is emerging for ROS as mediators of signaling pathways leading to cell proliferation and tumor initiation and promotion. Complex and multifunctional relationships between these molecular events are being discovered which are leading researchers to believe that the tumor-promoting effects might be in relation to the tiny electric currents induced by ROS and transported through the cytoskeletal actin microfilament network [31]. As mentioned above, the regulation of ROS levels is very complex especially if one considers that ROS production is also under the control of the TP53 suppressor gene. The induction of apoptosis by p53 has been related to its capability to induce ROS production [32]. On the other hand, ROS are also known to be critical for senescence [33] and the p53 target genes that increase ROS may also play an important role in senescence induction. However, p53 also promotes the expression of a number of antioxidant genes, accounting for p53’s ability to control oxidative stress [34]. So p53’s ability to decrease or increase oxidative stress likely contributes to a dual effect on senescence. Another element to be taken into account is represented by the inhibition of mTOR pathway exerted by p53 that contributes to the antisenescence activity of this transcription factor [35]. Furthermore, mTOR can be activated by ROS [36], whereby p53’s antioxidant activities may reinforce the dampening of mTOR and senescence (Figure 1). Since there is good evidence that acetylation of p53 promotes senescence and apoptosis, it has been argued that inhibitors of the deacetylation enzymes might rescue p53 responses and be employed for cancer therapy [37]. The most accredited model indicates that mild stress induced by a physiological increase of cellular functions has an antioxidant response through a slight activation of p53, while a high p53 activity may induce apoptosis or senescence, thereby favoring aging. Mouse models also clearly suggest that inappropriate p53 activity promotes aging while a robust but normally regulated p53 response protects from the aging process. Therefore, the persistent stress observed in cancer would favor p53-induced senescence over a more transient cell cycle arrest [38].

Interestingly, a close interrelationship exists between oxidative stress and several stress response pathways. For example, an increase in the expression of certain inducible heat shock proteins (Hsps), particularly Hsp27, has been observed following oxidative stress [3941]. Hsps, apart from heat shock, have been reported to protect against several oxidants. In addition, activation of the UPR stimulates upregulation of antioxidant genes through protein kinase RNA- (PKR-) like ER kinase- (PERK-) dependent phosphorylation of the Nrf2 (also known as Nfe2l2) transcription factor, whose target genes include enzymes involved in GSH biosynthesis and heme oxygenase-1 [42]. This antioxidant activity is also involved in activation of the repressor protein for Nrf2, Keap1 [4346]. In contrast to the physiological regulation of Nrf2, in neoplasia there is evidence for increased basal activation of Nrf2. Indeed, somatic mutations that disrupt the Nrf2-Keap1 interaction, stabilize Nrf2, and activate Nrf2 target genes were found in cancer, indicating a role in tumorigenesis [47]. Interestingly, it has been shown that the Nfr2 transcription induced by endogenous oncogenic alleles of Kras, Braf, and Myc promotes ROS detoxification and cancer [48]. As ROS can cause damage to all of the major classes of biological macromolecules, including nucleic acids, proteins, carbohydrates, and lipids, when the cell’s antioxidant defenses are overwhelmed, cell death occurs. Numerous studies have shown that the oxidative balance affects not only cell fate, but also the mode of cell death [49, 50]. Many cytotoxic agents induce ROS, including peroxide and , which are involved in the induction of apoptotic cell death [51]. H2O2 can cause the release of cytochrome c from mitochondria with the activation of the intrinsic pathway of apoptosis but can also activate nuclear transcription factors, like NF-κB, AP-1, and p53 [52], which may upregulate death proteins or produce inhibitors of survival proteins. However, ROS are also reported to interfere with the apoptosis program, engaging cells to adopt an alternative mode of cell death. Apoptotic cell death can be switched to necrosis during oxidative stress by two possible mechanisms: inactivation of caspases or a drop in ATP levels. Caspases contain an active site cysteine nucleophile [53], which is prone to oxidation or thiol alkylation as well as S-nitrosylation [54]. This leads to their inactivation, switching the mode of cell death to necrosis [55]. However, altered redox status can promote tumor initiation and progression by blunting cell death pathways, so a prooxidant intracellular milieu has been linked to carcinogenesis and tumor promotion. To this end, increased signaling via the PI3K/Akt pathway has been shown to result in enhanced intracellular ROS generation [56]. Similarly, cancer cells that constitutively express oncogenic Ras have been reported to produce higher intracellular levels of and to be resistant to drug-induced apoptosis [57]. In many tumors it has been observed that Hsps, including Hsp90, Hsp70, and Hsp27, were closely linked to the activation of tyrosine kinases, namely, Akt, and the levels of oncogenic proteins, such as Ras and HER2, strongly involved in malignancy [58, 59]. These chaperones participate in carcinogenesis and in cell death resistance by blocking key effector molecules of the apoptotic pathways at the pre- and post-mitochondrial level [59]. Thus, targeting Hsps, for example, with chemical inhibitors, is currently under investigation as an anticancer strategy [58]. Complete failure to repair DNA damage as well as inherited or acquired defects in maintenance systems of the mammalian genome can lead to mutations [60]. In addition, such deficiencies in the DNA damage response can lead to carcinogenesis, but also promotion, progression, and resistance to therapeutic treatment [60]. It is intriguing to note how some hormone-dependent cancers are strictly correlated to the types of dietary fat. A diet low in total fat, saturated, monounsaturated, and polyunsaturated fat and rich in omega-3 fatty acids, vitamin C, vitamin E, lycopene, alpha-tocopherol, selenium, beta-carotene, and quercetin is inversely associated with prostate cancer risk [61, 62]. These data highlight that the beneficial effects of antioxidant nutrients in prevention of prostate cancer derive from being able to increase the antioxidant levels.

4. Natural Antioxidants Prevent UV-Induced Skin Carcinogenesis

The risks of skin carcinogenesis and melanomagenesis may be lowered through the modulation of UV-activated cell signalling pathways and/or generation of oxidative stress [63]. It has been amply reported that natural antioxidants can exert a protective effect against skin cancer induced by UV radiation [64]. Medium-wave- (UVB-) induced carcinogenesis in mice was suppressed when a green tea polyphenolic fraction was topically applied to the skin or orally administered in the drinking water [65, 66]. Similarly, other reports showed that both orally administered and topically applied vitamin E [67] as well as olive oil application [68] were able to prevent the UVB-induced skin carcinogenesis in mice. Again, the anticarcinogenic effects of several antioxidants were equally well documented against melanoma. The melanomagenesis was shown to be greatly affected by substances that have the potential to inhibit ROS generation, such as genistein [69], curcumin [70], and aerial part of P. thunbergiana [71]. It is worth noting that genistein can act also as an “epigenetic modulator” since it can affect key tumor-related gene expression and signal pathways through dynamic regulation of both DNA methylation and histone modification pathways [72]. In this regard, D’Angelo et al. [73] indicated that hydroxytyrosol (DOPET), the major antioxidant compound present in olive oil, is able to prevent ROS production, lipid peroxidation, and protein damage in a human melanoma cell line (M14) exposed to UVA irradiation. In such a way this antioxidant exerts a protective effect on melanoma cells by reducing the UVA-induced oxidative stress.

5. Oxidative Stress and Epigenetic Modifications

A link, even if indirect, between oxidative stress and epigenetic alterations of either protooncogenes or tumor suppressor genes is now well established. The DNA damage caused by ROS prevents the DNA methyltransferases (DNMTs) from acting on their specific substrates, leading to global hypomethylation [74] and genomic instability. On the other hand, very high rates of ROS can reduce the expression of glutathione-s-transferase P1(GSTP1) gene, the main antioxidant enzyme, by inducing the methyl-binding protein (MBP), HDAC, and DNMT complex to methylate the promoter. High ROS levels induce also the oxidation of guanine to 8-oxoG which is able to convert the N7 position of guanine from an acceptor into a donor of hydrogen bonding, as well as to replace the 8-proton with an oxygen atom. When 8-oxoG is adjacent to the 5-methylcytosine MBP binding is weakened. Moreover, the observed frequent conversion of 5-methyl-cytosine into 5-hydroxymethyl-cytosine alters the binding affinity to MBPs resulting in epigenetic changes [75]. Generally, DNA methylation leads to gene silencing when particular and specific CpG islands are involved. In these cases the binding of transcriptional factors to their consensus sites is prevented [76]. Otherwise, the binding of methyl-binding domain proteins is favored leading to transcriptional repression through interaction with histone deacetylases (HDACs) [77, 78].

6. Impact of Oxidative Stress on Melanoma

Malignant melanoma, a neoplasm arising from malignant transformation of melanocytes, is predominantly a disease of the skin but may in rare instances occur at other sites, including the mucous membranes (hard palate, maxillary gingiva, lip, throat, esophagus, vulva, vagina, and perianal region) and the eye (uvea and retina). Like all tumor types there is considerable heterogeneity in outcome and molecular pathogenesis. Almost all histological and clinical patterns of melanoma are thought to be caused mainly by exposure to UV radiation, with their incidence being markedly increased in patients with a history of heavy sun exposure, or isolated episodes of serious sunburn [79]. In contrast, mucosal and soft tissue presentations of melanoma appear to have a distinct pathogenesis, as their growth might be independent of UV-linked pathways [80]. Really, the MAPK and phosphatidylinositol 3 (PI3) kinase pathways are involved differently between types or subtypes of melanoma classified according to sun exposure and anatomic site [81]. Consequently the genes concerned with these distinct pathways are differently involved, as mutations of BRAF [82] and NRAS [83] prevail in melanoma that occurs at sites intermittently exposed to UV, while a high frequency of mutations in specific exons of KIT is found at chronically sun-exposed or sun-protected sites, such as the mucous membranes [83]. UV can induce DNA damage through direct as well as mediated mechanisms. Mutagenic cyclobutane pyrimidine dimers, 6–4 photoproducts, DNA strand breaks, and DNA crosslinks are the direct consequences of UVB action. If not repaired properly, this DNA damage can result in mutations in the genome, ultimately contributing to skin carcinogenesis [84]. On the contrary, UVA rays are mostly responsible for DNA damage mediated by oxidative stress. However, both UVA and UVB have been shown to be responsible for photocarcinogenesis and photoimmunosuppression [85]. Epidemiological data strongly support the photoprotective role of melanin, as an inverse correlation between skin pigmentation and the incidence of sun-induced skin cancers was reported [86]. The shielding effect of melanin, especially eumelanin, is achieved by its ability to serve as a physical barrier that scatters UV radiation and an absorbent filter that reduces the penetration of UV through the epidermis [87]. DNA damage occurs to a greater extent in the upper layers of the epidermis, while the lower layers of the skin are protected as the melanin content of the skin increases [88]. Indeed, UV radiation induces less DNA damage and higher rate of apoptosis of damaged cells in darker skin than in lighter skin, a combination that results in a greatly reduced risk of carcinogenesis [88]. Another key mechanism through which UV induce melanomagenesis is the production of ROS. UV induce a dose-dependent response by human melanocytes leading to production of H2O2 [89], decrease in catalase activity, and reduced HO-1 expression [9094]. Similarly, it has been established that there is a role of ROS in the cell damage caused by UV radiation [68, 95]. The vulnerability of melanocytes to oxidative stress can be explained by their greater ability to produce ROS compared with keratinocytes and fibroblasts due to melanin production [96]. In fact, the melanosome is thought to be the main source of the high levels of ROS observed either in melanocytes or in melanoma cells [97102]. This hypothesis is strengthened by a higher expression of either 8-hydroxydeoxyguanosine (8-OHdG), a major form of oxidative DNA damage, or base excision repair (BER) genes in melanocytes with respect to keratinocytes [103], as well as by the decrease in ROS levels following inhibition of melanin synthesis [100]. However, there are conflicting data in the literature on the prooxidant and antioxidant effects exerted by melanin. Some studies showed that the levels of H2O2 after exposure to UV are inversely related to the amount of melanin, which would thus possess an antioxidant effect [92]. Similarly, further findings indicated that induction of melanogenesis increases the activity and expression of catalase, thus inhibiting UV-induced H2O2 generation [92, 104], and others reported that more pronounced pigmentation protects against UV- or H2O2-induced mitochondrial DNA damage [105]. In contrast, stimulation of melanogenesis is reported to promote oxidative DNA damage in human melanocytes or mouse melanoma cells [106108].

Oxidative stress can throw off the balance of homeostasis in melanocytes, threatening their survival or inducing malignant transformation [96]. It has been reported that subunits of the NADPH oxidase (NOX) enzyme complex are strongly involved in the generation of oxidative stress and expressed in primary and metastatic melanoma cells at a higher level than in normal human melanocytes [109, 110]. In addition, NOX1 activity and protein levels increased after UV exposure in primary melanoma cells [109, 111] and may be responsible for ROS accumulation in dysplastic nevi [111]. Moreover, it was demonstrated that the expression of the neuronal form of nitric oxide synthase (nNOS) is higher in melanoma cells than in normal melanocytes [112] and that its suppression reduces xenografted melanoma tumor growth and metastatic potential in vivo [112, 113]. It is noteworthy that toxicity of reactive nitrogen species (RNS) dramatically increases in the presence of ROS [114], constituting a deleterious mix that may initiate melanomagenesis owing to the leaking of melanosome contents. The importance of oxidative stress in melanoma is reinforced by the findings that mutations in several melanoma-associated genes result from or worsen oxidative stress. For example, the somatic BRAF V600E mutation, normally occurring in nevi and melanoma, can be oxidative stress-induced [115] and loss of p16 expression, commonly observed in melanoma, leads to dramatic increases in ROS levels in cultured human melanocytes [116]. Moreover, melanoma progression is associated with depletion of PTEN and the resulting increase in superoxide anion [117]. In addition, the polymorphism GSTP1 rs1695 [118] and the combined GSTM1 and GSTT1 null polymorphisms [119] have been associated with melanoma susceptibility and with further increase in melanoma risk. These findings strongly indicate that oxidative stress is a driver of melanomagenesis [120].

7. Oxidative Stress Modulates DNA Methylation in Melanomagenesis

It was at first expected that aberrant DNA methylation would be infrequently implicated in melanomagenesis, as UV irradiation—that is deeply involved in melanoma—is believed to mainly cause gene mutations rather than epimutations. However, unexpectedly, epigenetic silencing of various tumour suppressor genes has been so far observed during melanoma development, progression, and metastasis [121125]. Melanoma exhibits either global hypomethylation or local hypermethylation at the tumour suppressor gene level [126128]. Nonetheless, the degree of global hypomethylation does not discriminate benign nevus from melanoma [129], as instead the survey on specific hypermethylation of tumor suppressor genes does [130, 131]. In this regard, we have shown that a high frequency of hypermethylation of p16INK4A [132], DcR1, and DcR2 [133] promoters occurred in cutaneous as well as uveal melanoma. However, the search for specific sites of hypermethylation in melanoma also allowed us to identify a different susceptibility of uveal and cutaneous melanoma to the epigenetic effects of cadmium. In fact, we showed that cadmium exposure led to aberrant methylation and silencing of in uveal melanoma, hypermethylation, and deregulation of caspase 8 in cutaneous melanoma cells [134]. Epigenetic processes, such as DNA promoter methylation and histone acetylation/deacetylation, were shown to be key cellular events during tumorigenesis [135, 136], and particularly in melanogenesis, since melanoma cells employ the epigenetic machinery to cope with adverse events and acquire resistance to chemotherapeutics [137]. This is particularly intriguing in view of the excellent response to treatment with epidrugs by patients with mucosal and ocular melanoma, which are the forms of melanoma more resistant to chemotherapy [138]. The combined therapy with the DNMT and HDAC inhibitors, decitabine and panobinostat, and the chemotherapeutic agent temozolomide has proven to be very effective. Moreover, a complete response was obtained in one patient affected by mucosal melanoma after only two cycles. This result is of particular relevance, since, as mentioned, mucosal melanomas harbor KIT mutations, are generally negative for BRAF, and metastasize more frequently than cutaneous melanomas. Therefore, further studies on epigenetic modifications that occur in mucosal melanomas and the possibility of reverting these changes with specific epidrugs become crucial, even if the rarity of these tumors can hinder studying this melanoma subtype. DNMT inhibition followed by HDAC inhibition, and targeting key epigenetic events, could turn on or off specific pathways that confer resistance to chemotherapy and apoptosis. Although oxidative/nitrosative stress and changes in DNA methylation were observed in many tumor types, few reports are available about the correlation between these events and melanomagenesis. Recently, methylated genes implicated in the response to oxidative damage have been associated with the risk of developing melanoma or dysplastic nevi [139], thus suggesting a link between oxidative imbalance and hypermethylation in melanoma. A previous study has shown that the blockade of a melanocyte cell line anchorage to extracellular matrix resulted in increased ROS and levels [140]. These alterations were accompanied by an increase in GSH and malondialdehyde (MDA) levels and methylated DNA content due to an upregulation of DNMT1 and DNMT3b expression. The NOS inhibitor N(G)-Nitro-L-arginine methyl ester (L-NAME) and -acetyl-L-cysteine (NAC) abrogate either the DNA hypermethylation or the production of superoxide anion. Although increased ROS intracellular levels induced by anchorage blockade have been considered as mediators of anoikis of several cell types [141, 142], they have also been associated with protection from apoptosis [57, 143]. Therefore, it can be argued that the decision to turn on the pathways of survival or death can be determined by the levels of ERK or p53, respectively [140]. Of particular significance is the presence of relevant amounts of p53 only in premalignant and not in malignant melanoma cells [140]. The mechanisms by which the oxidative stress induced in premalignant melanocytes by deadhesion modulates DNA methylation pattern and induces cell transformation have been recently elucidated through elegant experiments performed by Molognoni et al. [144]. They were able to show that melanocyte deadhesion increases superoxide anion levels and DNMT1 production as well as global DNA hypermethylation. The increase in superoxide anion is caused by the activation of Rac1 and leads to the activation of Ras pathway, which in turn activates Rac1. DNMT1 upregulation, global DNA methylation, and malignant transformation are achieved by Ras-induced ERK activation. The sequence of events triggered by the deadhesion of the melanocytic line melan-a is described in Figure 2.

Taken together, these findings have delineated the ways by which the oxidative stress induced by disanchorage of melanocytes from extracellular matrix may modify the epigenetic machinery and lead to melanoma. Thus, the aberrant oxidative pathways associate with sustained levels of stress, which might or might not be related to UV exposure, and appear to contribute to the development of melanoma through epimutations.

8. Conclusions

Melanocytes are particularly susceptible to oxidative stress owing to the prooxidant state generated during melanin synthesis and to the intrinsic antioxidant defenses that may be shattered in pathologic conditions. Oxidative stress can disrupt the homeostasis of melanocytes, causing damage to DNA, protein, and cellular components. Altered ROS levels could also affect epigenetic mechanisms and promote alterations in gene expression, thus leading to severe impairment of cell survival and cancer development. Understanding the complexity of oxidative stress pathways regulating the production of pigmentation, melanocyte growth, and malignant transformation has great potential to define the plethora of clinically effective compounds and give enormous promise for patients affected by this disease. A combinatorial strategy of epigenetic therapy with agents able to prevent the production and chronic accumulation of ROS along with standard chemotherapeutic regimens may help in overriding the intrinsic melanoma resistance to current approaches of treatment and hindering its recurrence.

Conflict of Interests

The authors confirm that this paper content has no conflict of interests.

Authors’ Contribution

Mario Venza and Maria Visalli contributed equally to this work and therefore should be considered equal first authors.


  1. M. Sattler, T. Winkler, S. Verma et al., “Hematopoietic growth factors signal through the formation of reactive oxygen species,” Blood, vol. 93, no. 9, pp. 2928–2935, 1999. View at: Google Scholar
  2. L. K. Kwong and R. S. Sohal, “Substrate and site specificity of hydrogen peroxide generation in mouse mitochondria,” Archives of Biochemistry and Biophysics, vol. 350, no. 1, pp. 118–126, 1998. View at: Publisher Site | Google Scholar
  3. M. Mérad-Saïdoune, E. Boitier, A. Nicole et al., “Overproduction of Cu/Zn-superoxide dismutase or Bcl-2 prevents the brain mitochondrial respiratory dysfunction induced by glutathione depletion,” Experimental Neurology, vol. 158, no. 2, pp. 428–436, 1999. View at: Publisher Site | Google Scholar
  4. R. H. Burdon, “Superoxide and hydrogen peroxide in relation to mammalian cell proliferation,” Free Radical Biology and Medicine, vol. 18, no. 4, pp. 775–794, 1995. View at: Publisher Site | Google Scholar
  5. Y. S. Bae, S. W. Kang, M. S. Seo et al., “Epidermal growth factor (EGF)-induced generation of hydrogen peroxide. Role in EGF receptor-mediated tyrosine phosphorylation,” The Journal of Biological Chemistry, vol. 272, no. 1, pp. 217–221, 1997. View at: Publisher Site | Google Scholar
  6. W. Dröge, “Free radicals in the physiological control of cell function,” Physiological Reviews, vol. 82, no. 1, pp. 47–95, 2002. View at: Google Scholar
  7. D. M. Hockenbery, Z. N. Oltvai, X.-M. Yin, C. L. Milliman, and S. J. Korsmeyer, “Bcl-2 functions in an antioxidant pathway to prevent apoptosis,” Cell, vol. 75, no. 2, pp. 241–251, 1993. View at: Publisher Site | Google Scholar
  8. X. Deng, L. Xiao, W. Lang, F. Gao, P. Ruvolo, and W. S. May, “Novel Role for JNK as a Stress-activated Bcl2 Kinase,” Journal of Biological Chemistry, vol. 276, no. 26, pp. 23681–23688, 2001. View at: Publisher Site | Google Scholar
  9. X. Deng, P. Ruvolo, B. K. Carr, and W. S. May Jr., “Survival function of ERK1/2 as IL-3-activated, staurosporine-resistant Bcl2 kinases,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 4, pp. 1578–1583, 2000. View at: Publisher Site | Google Scholar
  10. S. Coats, W. M. Flanagan, J. Nourse, and J. M. Roberts, “Requirement of p27Kip1 for restriction point control of the fibroblast cell cycle,” Science, vol. 272, no. 5263, pp. 877–880, 1996. View at: Publisher Site | Google Scholar
  11. N. Rivard, G. L'Allemain, J. Bartek, and J. Pouysségur, “Abrogation of p27Kip1 by cDNA antisense suppresses quiescence (G0 state) in fibroblasts,” The Journal of Biological Chemistry, vol. 271, no. 31, pp. 18337–18341, 1996. View at: Publisher Site | Google Scholar
  12. X. Deng, F. Gao, and W. S. May Jr., “Bcl2 retards G1/S cell cycle transition by regulating intracellular ROS,” Blood, vol. 102, no. 9, pp. 3179–3185, 2003. View at: Publisher Site | Google Scholar
  13. I. L. Ibañez, C. Bracalente, C. Notcovich et al., “Phosphorylation and subcellular localization of p27Kip1 regulated by hydrogen peroxide modulation in cancer cells,” PLoS ONE, vol. 7, no. 9, Article ID e44502, 2012. View at: Publisher Site | Google Scholar
  14. C. Holohan, E. Szegezdi, T. Ritter, T. O'Brien, and A. Samali, “Cytokine-induced β-cell apoptosis is NO-dependent, mitochondria-mediated and inhibited by BCL-XL: apoptosis,” Journal of Cellular and Molecular Medicine, vol. 12, no. 2, pp. 591–606, 2008. View at: Publisher Site | β-cell%20apoptosis%20is%20NO-dependent,%20mitochondria-mediated%20and%20inhibited%20by%20BCL-XL:%20apoptosis&author=C. Holohan&author=E. Szegezdi&author=T. Ritter&author=T. O'Brien&author=&author=A. Samali&publication_year=2008" target="_blank">Google Scholar
  15. S. Lortz, E. Gurgul-Convey, S. Lenzen, and M. Tiedge, “Importance of mitochondrial superoxide dismutase expression in insulin-producing cells for the toxicity of reactive oxygen species and proinflammatory cytokines,” Diabetologia, vol. 48, no. 8, pp. 1541–1548, 2005. View at: Publisher Site | Google Scholar
  16. I. Kharroubi, L. Ladrière, A. K. Cardozo, Z. Dogusan, M. Cnop, and D. L. Eizirik, “Free fatty acids and cytokines induce pancreatic β-cell apoptosis by different mechanisms: role of nuclear factor-κB and endoplasmic reticulum stress,” Endocrinology, vol. 145, no. 11, pp. 5087–5096, 2004. View at: Publisher Site | Google Scholar
  17. R. Banerjee, A. A. Starkov, M. F. Beal, and B. Thomas, “Mitochondrial dysfunction in the limelight of Parkinson's disease pathogenesis,” Biochimica et Biophysica Acta, vol. 1792, no. 7, pp. 651–663, 2009. View at: Publisher Site | Google Scholar
  18. S. Fulda, A. M. Gorman, O. Hori, and A. Samali, “Cellular stress responses: cell survival and cell death,” International Journal of Cell Biology, vol. 2010, Article ID 214074, 23 pages, 2010. View at: Publisher Site | Google Scholar
  19. M. A. Pappolla, Y.-J. Chyan, R. A. Omar et al., “Evidence of oxidative stress and in vivo neurotoxicity of β-amyloid in a transgenic mouse model of Alzheimer's disease: a chronic oxidative paradigm for testing antioxidant therapies in vivo,” The American Journal of Pathology, vol. 152, no. 4, pp. 871–877, 1998. View at: Google Scholar
  20. M. A. Smith, K. Hirai, K. Hsiao et al., “Amyloid-β deposition in Alzheimer transgenic mice is associated with oxidative stress,” Journal of Neurochemistry, vol. 70, no. 5, pp. 2212–2215, 1998. View at: β%20deposition%20in%20Alzheimer%20transgenic%20mice%20is%20associated%20with%20oxidative%20stress&author=M. A. Smith&author=K. Hirai&author=K. Hsiao et al.&publication_year=1998" target="_blank">Google Scholar
  21. D. A. Butterfield, A. Castegna, C. M. Lauderback, and J. Drake, “Evidence that amyloid beta-peptide-induced lipid peroxidation and its sequelae in Alzheimer's disease brain contribute to neuronal death,” Neurobiology of Aging, vol. 23, no. 5, pp. 655–664, 2002. View at: Publisher Site | Google Scholar
  22. W. R. Markesbery, “Oxidative stress hypothesis in Alzheimer's disease,” Free Radical Biology & Medicine, vol. 23, no. 1, pp. 134–147, 1997. View at: Publisher Site | Google Scholar
  23. A. M. Gorman, “Neuronal cell death in neurodegenerative diseases: recurring themes around protein handling: Apoptosis Review Series,” Journal of Cellular and Molecular Medicine, vol. 12, no. 6, pp. 2263–2280, 2008. View at: Publisher Site | Google Scholar
  24. V. Della Bianca, S. Dusi, E. Bianchini, I. Dal Prà, and F. Rossi, “β-amyloid activates the O2˙- forming NADPH oxidase in microglia, monocytes, and neutrophils. A possible inflammatory mechanism of neuronal damage in Alzheimer's disease,” Journal of Biological Chemistry, vol. 274, no. 22, pp. 15493–15499, 1999. View at: Publisher Site | β-amyloid%20activates%20the%20O2˙-%20forming%20NADPH%20oxidase%20in%20microglia,%20monocytes,%20and%20neutrophils.%20A%20possible%20inflammatory%20mechanism%20of%20neuronal%20damage%20in%20Alzheimer's%20disease&author=V. Della Bianca&author=S. Dusi&author=E. Bianchini&author=I. Dal Prà&author=&author=F. Rossi&publication_year=1999" target="_blank">Google Scholar
  25. J. M. Andersen, O. Myhre, H. Aarnes, T. A. Vestad, and F. Fonnum, “Identification of the hydroxyl radical and other reactive oxygen species in human neutrophil granulocytes exposed to a fragment of the amyloid beta peptide,” Free Radical Research, vol. 37, no. 3, pp. 269–279, 2003. View at: Publisher Site | Google Scholar
  26. S. E. Logue, A. B. Gustafsson, A. Samali, and R. A. Gottlieb, “Ischemia/reperfusion injury at the intersection with cell death,” Journal of Molecular and Cellular Cardiology, vol. 38, no. 1, pp. 21–33, 2005. View at: Publisher Site | Google Scholar
  27. R. von Harsdorf, P. F. Li, and R. Dietz, “Signaling pathways in reactive oxygen species-induced cardiomyocyte apoptosis,” Circulation, vol. 99, no. 22, pp. 2934–2941, 1999. View at: Publisher Site | Google Scholar
  28. I. Venza, M. Visalli, R. Oteri, D. Teti, and M. Venza, “Combined effects of cigarette smoking and alcohol consumption on antioxidant/oxidant balance in age-related macular degeneration,” Aging Clinical and Experimental Research, vol. 24, no. 5, pp. 530–536, 2012. View at: Publisher Site | Google Scholar
  29. I. Venza, M. Visalli, M. Cucinotta, D. Teti, and M. Venza, “Association between oxidative stress and macromolecular damage in elderly patients with age-related macular degeneration,” Aging Clinical and Experimental Research, vol. 24, no. 1, pp. 21–27, 2012. View at: Publisher Site | Google Scholar
  30. L. M. Ellerby, H. M. Ellerby, S. M. Park et al., “Shift of the cellular oxidation-reduction potential in neural cells expressing Bcl2,” Journal of Neurochemistry, vol. 67, no. 3, pp. 1259–1267, 1996. View at: Google Scholar
  31. G. Cavelier, “Theory of malignant cell transformation by superoxide fate coupled with cytoskeletal electron-transport and electron-transfer,” Medical Hypotheses, vol. 54, no. 1, pp. 95–98, 2000. View at: Publisher Site | Google Scholar
  32. T. M. Johnson, Z.-X. Yu, V. J. Ferrans, R. A. Lowenstein, and T. Finkel, “Reactive oxygen species are downstream mediators of p53-dependent apoptosis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 93, no. 21, pp. 11848–11852, 1996. View at: Publisher Site | Google Scholar
  33. T. Lu and T. Finkel, “Free radicals and senescence,” Experimental Cell Research, vol. 314, no. 9, pp. 1918–1922, 2008. View at: Publisher Site | Google Scholar
  34. I. A. Olovnikov, J. E. Kravchenko, and P. M. Chumakov, “Homeostatic functions of the p53 tumor suppressor: regulation of energy metabolism and antioxidant defense,” Seminars in Cancer Biology, vol. 19, no. 1, pp. 32–41, 2009. View at: Publisher Site | Google Scholar
  35. L. G. Korotchkina, O. V. Leontieva, E. I. Bukreeva, Z. N. Demidenko, A. V. Gudkov, and M. V. Blagosklonny, “The choice between p53-induced senescence and quiescence is determined in part by the mTOR pathway,” Aging, vol. 2, no. 6, pp. 344–352, 2010. View at: Google Scholar
  36. M. V. Blagosklonny, “Aging: ROS or TOR,” Cell Cycle, vol. 7, no. 21, pp. 3344–3354, 2008. View at: Publisher Site | Google Scholar
  37. S. Lain, J. J. Hollick, J. Campbell et al., “Discovery, in vivo activity, and mechanism of action of a small-molecule p53 activator,” Cancer Cell, vol. 13, no. 5, pp. 454–463, 2008. View at: Publisher Site | Google Scholar
  38. A. Vigneron and K. H. Vousden, “p53, ROS and senescence in the control of aging,” Aging, vol. 2, no. 8, pp. 471–474, 2010. View at: Google Scholar
  39. A. M. Gorman, B. Heavey, E. Creagh, T. G. Cotter, and A. Samali, “Antioxidant-mediated inhibition of the heat shock response leads to apoptosis,” FEBS Letters, vol. 445, no. 1, pp. 98–102, 1999. View at: Publisher Site | Google Scholar
  40. A. M. Gorman, E. Szegezdi, D. J. Quigney, and A. Samali, “Hsp27 inhibits 6-hydroxydopamine-induced cytochrome c release and apoptosis in PC12 cells,” Biochemical & Biophysical Research Communications, vol. 327, no. 3, pp. 801–810, 2005. View at: Publisher Site | Google Scholar
  41. W. R. Swindell, M. Huebner, and A. P. Weber, “Transcriptional profiling of Arabidopsis heat shock proteins and transcription factors reveals extensive overlap between heat and non-heat stress response pathways,” BMC Genomics, vol. 8, article 125, 2007. View at: Publisher Site | Google Scholar
  42. S. B. Cullinan and J. A. Diehl, “Coordination of ER and oxidative stress signaling: the PERK/Nrf2 signaling pathway,” International Journal of Biochemistry & Cell Biology, vol. 38, no. 3, pp. 317–332, 2006. View at: Publisher Site | Google Scholar
  43. K. Itoh, N. Wakabayashi, Y. Katoh et al., “Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain,” Genes & Development, vol. 13, no. 1, pp. 76–86, 1999. View at: Publisher Site | Google Scholar
  44. N. Wakabayashi, K. Itoh, J. Wakabayashi et al., “Keap1-null mutation leads to postnatal lethality due to constitutive Nrf2 activation,” Nature Genetics, vol. 35, no. 3, pp. 238–245, 2003. View at: Publisher Site | Google Scholar
  45. T. Nguyen, P. Nioi, and C. B. Pickett, “The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress,” The Journal of Biological Chemistry, vol. 284, no. 20, pp. 13291–13295, 2009. View at: Publisher Site | Google Scholar
  46. R. Venugopal and A. K. Jaiswal, “Nrf2 and Nrf1 in association with Jun proteins regulate antioxidant response element-mediated expression and coordinated induction of genes encoding detoxifying enzymes,” Oncogene, vol. 17, no. 24, pp. 3145–3156, 1998. View at: Publisher Site | Google Scholar
  47. J. D. Hayes and M. McMahon, “NRF2 and KEAP1 mutations: permanent activation of an adaptive response in cancer,” Trends in Biochemical Sciences, vol. 34, no. 4, pp. 176–188, 2009. View at: Publisher Site | Google Scholar
  48. G. M. Denicola, F. A. Karreth, T. J. Humpton et al., “Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis,” Nature, vol. 475, no. 7354, pp. 106–109, 2011. View at: Publisher Site | Google Scholar
  49. D. Trachootham, W. Lu, M. A. Ogasawara, N. R.-D. Valle, and P. Huang, “Redox regulation of cell survival,” Antioxidants & Redox Signaling, vol. 10, no. 8, pp. 1343–1374, 2008. View at: Publisher Site | Google Scholar
  50. M. Genestra, “Oxyl radicals, redox-sensitive signalling cascades and antioxidants,” Cellular Signalling, vol. 19, no. 9, pp. 1807–1819, 2007. View at: Publisher Site | Google Scholar
  51. A. Gorman, A. McGowan, and T. G. Cotter, “Role of peroxide and superoxide anion during tumour cell apoptosis,” FEBS Letters, vol. 404, no. 1, pp. 27–33, 1997. View at: Publisher Site | Google Scholar
  52. M. Meyer, R. Schreck, and P. A. Baeuerle, “H2O2 and antioxidants have opposite effects on activation of NF-κB and AP-1 in intact cells: AP-1 as secondary antioxidantresponsive factor,” EMBO Journal, vol. 12, no. 5, pp. 2005–2015, 1993. View at: Google Scholar
  53. E. S. Alnemri, D. J. Livingston, D. W. Nicholson et al., “Human ICE/CED-3 protease nomenclature,” Cell, vol. 87, no. 2, p. 171, 1996. View at: Publisher Site | Google Scholar
  54. J. Chandra, A. Samali, and S. Orrenius, “Triggering and modulation of apoptosis by oxidative stress,” Free Radical Biology & Medicine, vol. 29, no. 3-4, pp. 323–333, 2000. View at: Publisher Site | Google Scholar
  55. A. Samali, H. Nordgren, B. Zhivotovsky, E. Peterson, and S. Orrenius, “A comparative study of apoptosis and necrosis in HepG2 cells: oxidant-induced caspase inactivation leads to necrosis,” Biochemical and Biophysical Research Communications, vol. 255, no. 1, pp. 6–11, 1999. View at: Publisher Site | Google Scholar
  56. S. Qin and P. B. Chock, “Implication of phosphatidylinositol 3-kinase membrane recruitment in hydrogen peroxide-induced activation of PI3K and Akt,” Biochemistry, vol. 42, no. 10, pp. 2995–3003, 2003. View at: Publisher Site | Google Scholar
  57. S. Pervaiz, J. Cao, O. S. P. Chao, Y. Y. Chin, and M. V. Clément, “Activation of the RacGTPase inhibits apoptosis in human tumor cells,” Oncogene, vol. 20, no. 43, pp. 6263–6268, 2001. View at: Publisher Site | Google Scholar
  58. D. Mahalingam, R. Swords, J. S. Carew, S. T. Nawrocki, K. Bhalla, and F. J. Giles, “Targeting HSP90 for cancer therapy,” British Journal of Cancer, vol. 100, no. 10, pp. 1523–1529, 2009. View at: Publisher Site | Google Scholar
  59. C. Garrido, M. Brunet, C. Didelot, Y. Zermati, E. Schmitt, and G. Kroemer, “Heat shock proteins 27 and 70: anti-apoptotic proteins with tumorigenic properties,” Cell Cycle, vol. 5, no. 22, pp. 2592–2601, 2006. View at: Publisher Site | Google Scholar
  60. J. H. J. Hoeijmakers, “Genome maintenance mechanisms for preventing cancer,” Nature, vol. 411, no. 6835, pp. 366–374, 2001. View at: Publisher Site | Google Scholar
  61. M. Messina and J. W. Erdman Jr., “Need to establish threshold soy protein intake for cholesterol reduction,” The American Journal of Clinical Nutrition, vol. 81, no. 4, pp. 942–943, 2005. View at: Google Scholar
  62. W. J. Craig, “Health effects of vegan diets,” The American Journal of Clinical Nutrition, vol. 89, no. 5, pp. 1627S–1633S, 2009. View at: Publisher Site | Google Scholar
  63. V. Muthusamy, L. D. Hodges, T. A. MacRides, G. M. Boyle, and T. J. Piva, “Effect of novel marine nutraceuticals on IL-1α-mediated TNF-α release from UVB-irradiated human melanocyte-derived cells,” Oxidative Medicine and Cellular Longevity, vol. 2011, Article ID 728645, 11 pages, 2011. View at: Publisher Site | Google Scholar
  64. F. Afaq, V. M. Adhami, N. Ahmad, and H. Mukhtar, “Botanical antioxidants for chemoprevention of photocarcinogenesis,” Frontiers in Bioscience, vol. 7, pp. 784–792, 2002. View at: Publisher Site | Google Scholar
  65. Z. Y. Wang, R. Agarwal, D. R. Bickers, and H. Mukhtar, “Protection against ultraviolet B radiation-induced photocarcinogenesis in hairless mice by green tea polyphenols,” Carcinogenesis, vol. 12, no. 8, pp. 1527–1530, 1991. View at: Publisher Site | Google Scholar
  66. N. Ahmad and H. Mukhtar, “Green tea polyphenols and cancer: biologic mechanisms and practical implications,” Nutrition Reviews, vol. 57, no. 3, pp. 78–83, 1999. View at: Google Scholar
  67. D. C. Liebler and J. A. Burr, “Effects of UV light and tumor promoters on endogenous vitamin E status in mouse skin,” Carcinogenesis, vol. 21, no. 2, pp. 221–225, 2000. View at: Publisher Site | Google Scholar
  68. M. Ichihashi, M. Ueda, A. Budiyanto et al., “UV-induced skin damage,” Toxicology, vol. 189, no. 1-2, pp. 21–39, 2003. View at: Publisher Site | Google Scholar
  69. E.-S. Yang, J.-S. Hwang, H.-C. Choi, R.-H. Hong, and S.-M. Kang, “The effect of genistein on melanin synthesis and in vivo whitening,” Korean Journal of Microbiology and Biotechnology, vol. 36, no. 1, pp. 72–81, 2008. View at: Google Scholar
  70. R.-J. Shiau, J.-Y. Wu, S.-J. Chiou, and Y.-D. Wen, “Effects of curcumin on nitrosyl-iron complex-mediated DNA cleavage and cytotoxicity,” Planta Medica, vol. 78, no. 12, pp. 1342–1350, 2012. View at: Publisher Site | Google Scholar
  71. E. Han, B. Chang, D. Kim, H. Cho, and S. Kim, “Melanogenesis inhibitory effect of aerial part of Pueraria thunbergiana in vitro and in vivo,” Archives of Dermatological Research, vol. 307, no. 1, pp. 57–72, 2015. View at: Publisher Site | Google Scholar
  72. Y. Li, S. N. Saldanha, and T. O. Tollefsbol, “Impact of epigenetic dietary compounds on transgenerational prevention of human diseases,” AAPS Journal, vol. 16, no. 1, pp. 27–36, 2014. View at: Publisher Site | Google Scholar
  73. S. D'Angelo, D. Ingrosso, V. Migliardi et al., “Hydroxytyrosol, a natural antioxidant from olive oil, prevents protein damage induced by long-wave ultraviolet radiation in melanoma cells,” Free Radical Biology & Medicine, vol. 38, no. 7, pp. 908–919, 2005. View at: Publisher Site | Google Scholar
  74. J. T. Wachsman, “DNA methylation and the association between genetic and epigenetic changes: relation to carcinogenesis,” Mutation Research: Fundamental and Molecular Mechanisms of Mutagenesis, vol. 375, no. 1, pp. 1–8, 1997. View at: Publisher Site | Google Scholar
  75. K. V. Donkena, C. Y. Young, and D. J. Tindall, “Oxidative stress and DNA methylation in prostate cancer,” Obstetrics and Gynecology International, vol. 2010, Article ID 302051, 14 pages, 2010. View at: Publisher Site | Google Scholar
  76. G. C. Prendergast and E. B. Ziff, “Methylation-sensitive sequence-specific DNA binding by the c-Myc basic region,” Science, vol. 251, no. 4990, pp. 186–189, 1991. View at: Publisher Site | Google Scholar
  77. P. L. Jones, G. J. C. Veenstra, P. A. Wade et al., “Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription,” Nature Genetics, vol. 19, no. 2, pp. 187–191, 1998. View at: Publisher Site | Google Scholar
  78. X. Nan, H.-H. Ng, C. A. Johnson et al., “Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex,” Nature, vol. 393, no. 6683, pp. 386–389, 1998. View at: Publisher Site | Google Scholar
  79. V. Bataille, “Sun exposure, sunbeds and sunscreens and melanoma. what are the controversies?” Current Oncology Reports, vol. 15, no. 6, pp. 526–532, 2013. View at: Publisher Site | Google Scholar
  80. J. Rother and D. Jones, “Molecular markers of tumor progression in melanoma,” Current Genomics, vol. 10, no. 4, pp. 231–239, 2009. View at: Publisher Site | Google Scholar
  81. J. A. Curtin, J. Fridlyand, T. Kageshita et al., “Distinct sets of genetic alterations in melanoma,” The New England Journal of Medicine, vol. 353, no. 20, pp. 2135–2147, 2005. View at: Publisher Site | Google Scholar
  82. C. R. Antonescu, K. J. Busam, T. D. Francone et al., “L576P KIT mutation in anal melanomas correlates with KIT protein expression and is sensitive to specific kinase inhibition,” International Journal of Cancer, vol. 121, no. 2, pp. 257–264, 2007. View at: Publisher Site | Google Scholar
  83. J. A. Curtin, K. Busam, D. Pinkel, and B. C. Bastian, “Somatic activation of KIT in distinct subtypes of melanoma,” Journal of Clinical Oncology, vol. 24, no. 26, pp. 4340–4346, 2006. View at: Publisher Site | Google Scholar
  84. Y. Kim and Y.-Y. He, “Ultraviolet radiation-induced non-melanoma skin cancer: regulation of DNA damage repair and inflammation,” Genes & Diseases, vol. 1, no. 2, pp. 188–198, 2014. View at: Publisher Site | Google Scholar
  85. J. D'Orazio, S. Jarrett, A. Amaro-Ortiz, and T. Scott, “UV radiation and the skin,” International Journal of Molecular Sciences, vol. 14, no. 6, pp. 12222–12248, 2013. View at: Publisher Site | Google Scholar
  86. J. Reichrath and K. Rass, “Ultraviolet damage, DNA repair and vitamin D in nonmelanoma skin cancer and in malignant melanoma: an update,” Advances in Experimental Medicine and Biology, vol. 810, pp. 208–233, 2014. View at: Google Scholar
  87. H. M. Gloster Jr. and K. Neal, “Skin cancer in skin of color,” Journal of the American Academy of Dermatology, vol. 55, no. 5, pp. 741–761, 2006. View at: Publisher Site | Google Scholar
  88. Y. Yamaguchi, K. Takahashi, B. Z. Zmudzka et al., “Human skin responses to UV radiation: pigment in the upper epidermis protects against DNA damage in the lower epidermis and facilitates apoptosis,” The FASEB Journal, vol. 20, no. 9, pp. 1486–1488, 2006. View at: Publisher Site | Google Scholar
  89. P. A. Van Der Kemp, J.-C. Blais, M. Bazin, S. Boiteux, and R. Santus, “Ultraviolet-B-induced inactivation of human OGG1, the repair enzyme for removal of 8-oxoguanine in DNA,” Photochemistry and Photobiology, vol. 76, no. 6, pp. 640–648, 2002. View at: Publisher Site | Google Scholar
  90. A. L. Kadekaro, R. Kavanagh, H. Kanto et al., “α-melanocortin and endothelin-1 activate antiapoptotic pathways and reduce DNA damage in human melanocytes,” Cancer Research, vol. 65, no. 10, pp. 4292–4299, 2005. View at: Publisher Site | Google Scholar
  91. A. Kokot, D. Metze, N. Mouchet et al., “alpha-melanocyte-stimulating hormone counteracts the suppressive effect of UVB on Nrf2 and Nrf-dependent gene expression in human skin,” Endocrinology, vol. 150, no. 7, pp. 3197–3206, 2009. View at: Publisher Site | Google Scholar
  92. X. Song, N. Mosby, J. Yang, A. Xu, Z. Abdel-Malek, and A. L. Kadekaro, “Alpha-MSH activates immediate defense responses to UV-induced oxidative stress in human melanocytes,” Pigment Cell & Melanoma Research, vol. 22, no. 6, pp. 809–818, 2009. View at: Publisher Site | Google Scholar
  93. A. L. Kadekaro, S. Leachman, R. J. Kavanagh et al., “Melanocortin 1 receptor genotype: an important determinant of the damage response of melanocytes to ultraviolet radiation,” The FASEB Journal, vol. 24, no. 10, pp. 3850–3860, 2010. View at: Publisher Site | Google Scholar
  94. A. L. Kadekaro, J. Chen, J. Yang et al., “Alpha-melanocyte-stimulating hormone suppresses oxidative stress through a p53-mediated signaling pathway in human melanocytes,” Molecular Cancer Research, vol. 10, no. 6, pp. 778–786, 2012. View at: Publisher Site | Google Scholar
  95. H. Chang, W. Oehrl, P. Elsner, and J. J. Thiele, “The role of H2O2 as a mediator of UVB-induced apoptosis in keratinocytes,” Free Radical Research, vol. 37, no. 6, pp. 655–663, 2003. View at: Publisher Site | Google Scholar
  96. L. Denat, A. L. Kadekaro, L. Marrot, S. A. Leachman, and Z. A. Abdel-Malek, “Melanocytes as instigators and victims of oxidative stress,” Journal of Investigative Dermatology, vol. 134, no. 6, pp. 1512–1518, 2014. View at: Publisher Site | Google Scholar
  97. F. L. Meyskens Jr., S. E. McNulty, J. A. Buckmeier et al., “Aberrant redox regulation in human metastatic melanoma cells compared to normal melanocytes,” Free Radical Biology & Medicine, vol. 31, no. 6, pp. 799–808, 2001. View at: Publisher Site | Google Scholar
  98. F. L. Meyskens Jr., P. Farmer, and J. P. Fruehauf, “Redox regulation in human melanocytes and melanoma,” Pigment Cell Research, vol. 14, no. 3, pp. 148–154, 2001. View at: Publisher Site | Google Scholar
  99. F. L. Meyskens Jr., H. van Chau, N. Tohidian, and J. Buckmeier, “Luminol-enhanced chemiluminescent response of human melanocytes and melanoma cells to hydrogen peroxide stress,” Pigment Cell Research, vol. 10, no. 3, pp. 184–189, 1997. View at: Publisher Site | Google Scholar
  100. N. C. Jenkins and D. Grossman, “Role of melanin in melanocyte dysregulation of reactive oxygen species,” BioMed Research International, vol. 2013, Article ID 908797, 3 pages, 2013. View at: Publisher Site | Google Scholar
  101. P. J. Farmer, S. Gidanian, B. Shahandeh, A. J. Di Bilio, N. Tohidian, and F. L. Meyskens Jr., “Melanin as a target for melanoma chemotherapy: pro-oxidant effect of oxygen and metals on melanoma viability,” Pigment Cell & Melanoma Research, vol. 16, no. 3, pp. 273–279, 2003. View at: Publisher Site | Google Scholar
  102. F. L. Meyskens Jr., P. J. Farmer, S. Yang, and H. Anton-Culver, “New perspectives on melanoma phatogenesis and chemoprevention,” Recent Results in Cancer Research, vol. 174, pp. 191–195, 2007. View at: Google Scholar
  103. S. Mouret, A. Forestier, and T. Douki, “The specificity of UVA-induced DNA damage in human melanocytes,” Photochemical and Photobiological Sciences, vol. 11, no. 1, pp. 155–162, 2012. View at: Publisher Site | Google Scholar
  104. V. Maresca, E. Flori, S. Briganti et al., “Correlation between melanogenic and catalase activity in in vitro human melanocytes: a synergic strategy against oxidative stress,” Pigment Cell & Melanoma Research, vol. 21, no. 2, pp. 200–205, 2008. View at: Publisher Site | Google Scholar
  105. H. Swalwell, J. Latimer, R. M. Haywood, and M. A. Birch-Machin, “Investigating the role of melanin in UVA/UVB- and hydrogen peroxide-induced cellular and mitochondrial ROS production and mitochondrial DNA damage in human melanoma cells,” Free Radical Biology and Medicine, vol. 52, no. 3, pp. 626–634, 2012. View at: Publisher Site | Google Scholar
  106. E. Wenczl, G. P. van der Schans, L. Roza et al., “(Pheo)melanin photosensitizes UVA-induced DNA damage in cultured human melanocytes,” Journal of Investigative Dermatology, vol. 111, no. 4, pp. 678–682, 1998. View at: Publisher Site | Google Scholar
  107. E. Kvam and R. M. Tyrrell, “The role of melanin in the induction of oxidative DNA base damage by ultraviolet A irradiation of DNA or melanoma cells,” Journal of Investigative Dermatology, vol. 113, no. 2, pp. 209–213, 1999. View at: Publisher Site | Google Scholar
  108. L. Marrot, J.-P. Belaidi, J.-R. Meunier, P. Perez, and C. Agapakis-Causse, “The human melanocyte as a particular target for UVA radiation and an endpoint for photoprotection assessment,” Photochemistry and Photobiology, vol. 69, no. 6, pp. 686–693, 1999. View at: Publisher Site | Google Scholar
  109. F. Liu, A. M. Gomez Garcia, and F. L. Meyskens, “NADPH oxidase 1 overexpression enhances invasion via matrix metalloproteinase-2 and epithelial-mesenchymal transition in melanoma cells,” Journal of Investigative Dermatology, vol. 132, no. 8, pp. 2033–2041, 2012. View at: Publisher Site | Google Scholar
  110. M. Yamaura, J. Mitsushita, S. Furuta et al., “NADPH oxidase 4 contributes to transformation phenotype of melanoma cells by regulating G2-M cell cycle progression,” Cancer Research, vol. 69, no. 6, pp. 2647–2654, 2009. View at: Publisher Site | Google Scholar
  111. F. Liu-Smith, R. Dellinger, and F. L. Meyskens Jr., “Updates of reactive oxygen species in melanoma etiology and progression,” Archives of Biochemistry and Biophysics, vol. 563, pp. 51–55, 2014. View at: Publisher Site | Google Scholar
  112. Z. Yang, B. Misner, H. Ji et al., “Targeting nitric oxide signaling with nNOS inhibitors as a novel strategy for the therapy and prevention of human melanoma,” Antioxidants & Redox Signaling, vol. 19, no. 5, pp. 433–447, 2013. View at: Publisher Site | Google Scholar
  113. H. Huang, H. Li, S. Yang et al., “Potent and selective double-headed thiophene-2-carboximidamide inhibitors of neuronal nitric oxide synthase for the treatment of melanoma,” Journal of Medicinal Chemistry, vol. 57, no. 3, pp. 686–700, 2014. View at: Publisher Site | Google Scholar
  114. S. Shiva, D. Moellering, A. Ramachandran et al., “Redox signalling: from nitric oxide to oxidized lipids,” Biochemical Society Symposium, vol. 71, pp. 107–120, 2004. View at: Google Scholar
  115. M. T. Landi, J. Bauer, R. M. Pfeiffer et al., “MC1R germline variants confer risk for BRAF-mutant melanoma,” Science, vol. 313, no. 5786, pp. 521–522, 2006. View at: Publisher Site | Google Scholar
  116. N. C. Jenkins, T. Liu, P. Cassidy et al., “The p16INK4A tumor suppressor regulates cellular oxidative stress,” Oncogene, vol. 30, no. 3, pp. 265–274, 2011. View at: Publisher Site | Google Scholar
  117. B. Govindarajan, J. E. Sligh, B. J. Vincent et al., “Overexpression of Akt converts radial growth melanoma to vertical growth melanoma,” The Journal of Clinical Investigation, vol. 117, no. 3, pp. 719–729, 2007. View at: Publisher Site | Google Scholar
  118. M. Ibarrola-Villava, M. Martin-Gonzalez, P. Lazaro, A. Pizarro, A. Lluch, and G. Ribas, “Role of glutathione S-transferases in melanoma susceptibility: association with GSTP1 rs1695 polymorphism,” British Journal of Dermatology, vol. 166, no. 6, pp. 1176–1183, 2012. View at: Publisher Site | Google Scholar
  119. C. Fortes, S. Mastroeni, P. Boffetta et al., “Polymorphisms of GSTM1 and GSTT1, sun exposure and the risk of melanoma: a case-control study,” Acta Dermato-Venereologica, vol. 91, no. 3, pp. 284–289, 2011. View at: Publisher Site | Google Scholar
  120. P. B. Cassidy, H. D. Fain, J. P. Cassidy Jr. et al., “Selenium for the prevention of cutaneous melanoma,” Nutrients, vol. 5, no. 3, pp. 725–749, 2013. View at: Publisher Site | Google Scholar
  121. T. Rothhammer and A.-K. Bosserhoff, “Epigenetic events in malignant melanoma,” Pigment Cell Research, vol. 20, no. 2, pp. 92–111, 2007. View at: Publisher Site | Google Scholar
  122. P. M. Howell Jr., S. Liu, S. Ren, C. Behlen, O. Fodstad, and A. I. Riker, “Epigenetics in human melanoma,” Cancer Control Journal, vol. 16, no. 3, pp. 200–218, 2009. View at: Google Scholar
  123. I. Venza, M. Visalli, R. Oteri, D. Teti, and M. Venza, “Class I-specific histone deacetylase inhibitor MS-275 overrides TRAIL-resistance in melanoma cells by downregulating c-FLIP,” International Immunopharmacology, vol. 21, no. 2, pp. 439–446, 2014. View at: Publisher Site | Google Scholar
  124. I. Venza, M. Visalli, R. Oteri, M. Cucinotta, D. Teti, and M. Venza, “Class II-specific histone deacetylase inhibitors MC1568 and MC1575 suppress IL-8 expression in human melanoma cells,” Pigment Cell and Melanoma Research, vol. 26, no. 2, pp. 193–204, 2013. View at: Publisher Site | Google Scholar
  125. M. Venza, C. Dell'Aversana, M. Visalli, L. Altucci, D. Teti, and I. Venza, “Identification of microRNA expression patterns in cutaneous and uveal melanoma cell lines,” Tumori, vol. 100, no. 1, pp. e4–e7, 2014. View at: Google Scholar
  126. D. S. B. Hoon, M. Spugnardi, C. Kuo, S. K. Huang, D. L. Morton, and B. Taback, “Profiling epigenetic inactivation of tumor suppressor genes in tumors and plasma from cutaneous melanoma patients,” Oncogene, vol. 23, no. 22, pp. 4014–4022, 2004. View at: Publisher Site | Google Scholar
  127. S. Liu, S. Ren, P. Howell, O. Fodstad, and A. I. Riker, “Identification of novel epigenetically modified genes in human melanoma via promoter methylation gene profiling,” Pigment Cell & Melanoma Research, vol. 21, no. 5, pp. 545–558, 2008. View at: Publisher Site | Google Scholar
  128. L. Shen, Y. Kondo, Y. Guo et al., “Genome-wide profiling of DNA methylation reveals a class of normally methylated CpG island promoters,” PLoS Genetics, vol. 3, no. 10, pp. 2023–2036, 2007. View at: Publisher Site | Google Scholar
  129. M. F. Paz, M. F. Fraga, S. Avila et al., “A systematic profile of DNA methylation in human cancer cell lines,” Cancer Research, vol. 63, no. 5, pp. 1114–1121, 2003. View at: Google Scholar
  130. K. Conway, S. N. Edmiston, Z. S. Khondker et al., “DNA-methylation profiling distinguishes malignant melanomas from benign nevi,” Pigment Cell & Melanoma Research, vol. 24, no. 2, pp. 352–360, 2011. View at: Publisher Site | Google Scholar
  131. S. Tellez, L. Shen, M. R. Estecio, J. Jelinek, J. E. Gershenwald, and J. P. J. Issa, “CpG island methylation profiling in human melanoma cell lines,” Melanoma Research, vol. 19, pp. 146–155, 2009. View at: Google Scholar
  132. M. Venza, M. Visalli, C. Biondo et al., “Epigenetic regulation of p14ARF and p16INK4A expression in cutaneous and uveal melanoma,” Biochimica et Biophysica Acta, vol. 1849, no. 3, pp. 247–256, 2015. View at: Publisher Site | Google Scholar
  133. M. Venza, M. Visalli, T. Catalano et al., “Impact of DNA methyltransferases on the epigenetic regulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor expression in malignant melanoma,” Biochemical and Biophysical Research Communications, vol. 441, no. 4, pp. 743–750, 2013. View at: Publisher Site | Google Scholar
  134. M. Venza, M. Visalli, C. Biondo et al., “Epigenetic marks responsible for cadmium-induced melanoma cell overgrowth,” Toxicology In Vitro, vol. 29, no. 1, pp. 242–250, 2015. View at: Publisher Site | Google Scholar
  135. S. B. Baylin and J. G. Herman, “DNA hypermethylation in tumorigenesis: epigenetics joins genetics,” Trends in Genetics, vol. 16, no. 4, pp. 168–174, 2000. View at: Publisher Site | Google Scholar
  136. I. Venza, M. Visalli, C. Fortunato et al., “PGE2 induces interleukin-8 derepression in human astrocytoma through coordinated DNA demethylation and histone hyperacetylation,” Epigenetics, vol. 7, no. 11, pp. 1315–1330, 2012. View at: Publisher Site | Google Scholar
  137. H. Röckmann and D. Schadendorf, “Drug resistance in human melanoma: mechanisms and therapeutic opportunities,” Onkologie, vol. 26, no. 6, pp. 581–587, 2003. View at: Publisher Site | Google Scholar
  138. C. Xia, R. Leon-Ferre, D. Laux et al., “Treatment of resistant metastatic melanoma using sequential epigenetic therapy (decitabine and panobinostat) combined with chemotherapy (temozolomide),” Cancer Chemotherapy and Pharmacology, vol. 74, no. 4, pp. 691–697, 2014. View at: Publisher Site | Google Scholar
  139. L. Pergoli, C. Favero, R. M. Pfeiffer et al., “Blood DNA methylation, nevi number, and the risk of melanoma,” Melanoma Research, vol. 24, no. 5, pp. 480–487, 2014. View at: Publisher Site | Google Scholar
  140. A. C. E. Campos, F. Molognoni, F. H. M. Melo et al., “Oxidative stress modulates DNA methylation during melanocyte anchorage blockade associated with malignant transformation,” Neoplasia, vol. 9, no. 12, pp. 1111–1121, 2007. View at: Publisher Site | Google Scholar
  141. N. Li, T. D. Oberley, L. W. Oberley, and W. Zhong, “Inhibition of cell growth in NIH/3T3 fibroblasts by overexpression of manganese superoxide dismutase: mechanistic studies,” Journal of Cellular Physiology, vol. 175, no. 3, pp. 359–369, 1998. View at: Publisher Site | Google Scholar
  142. L. M. Laguinge, S. Lin, R. N. Samara, A. N. Salesiotis, and J. M. Jessup, “Nitrosative stress in rotated three-dimensional colorectal carcinoma cell cultures induces microtubule depolymerization and apoptosis,” Cancer Research, vol. 64, no. 8, pp. 2643–2648, 2004. View at: Publisher Site | Google Scholar
  143. A. Laurent, C. Nicco, C. Chéreau et al., “Controlling tumor growth by modulating endogenous production of reactive oxygen species,” Cancer Research, vol. 65, no. 3, pp. 948–956, 2005. View at: Google Scholar
  144. F. Molognoni, F. H. M. de Melo, C. T. da Silva, and M. G. Jasiulionis, “Ras and Rac1, frequently mutated in melanomas, are activated by superoxide anion, modulate Dnmt1 level and are causally related to melanocyte malignant transformation,” PLoS ONE, vol. 8, no. 12, Article ID e81937, 2013. View at: Publisher Site | Google Scholar

Copyright © 2015 Mario Venza et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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