Oncogenic Metabolism Acts as a Prerequisite Step for Induction of Cancer Metastasis and Cancer Stem Cell Phenotype

Figure 2

Oncogenic metabolism plays an important role in the regulation of EMT. Four main mechanisms are involved in oncogenic metabolism-induced EMT: (1) regulation of both EMT and oncogenic metabolism by several transcription factors, (2) regulation of EMT by oncogenic enzymes and metabolites, (3) negative regulation of p53 by oncogenic metabolism, and (4) regulation of ROS and NADPH generation by oncogenic metabolism. (1) Several transcription factors and signaling factors involved in EMT or CSCs, including Snail, Dlx-2, HIF-1α, STAT3, TGF-β, Wnt, EGF, Notch, Hedgehog, hypoxia, and ROS, have been shown to regulate oncogenic metabolism. (2) PKM2 is translocated to the nucleus and then directly interacts with TGF-β-induced factor homeobox 2 (TGIF2) in colon cancer cells, thereby recruiting histone deacetylase 3 (HDAC3) to suppress E-cadherin transcription. PKM2 can also enhance tumor migration via PI3K/Akt signaling in gastric cancer. A FASN-TGF-β1-FASN-positive loop leads to high EMT/metastatic potential in cisplatin-resistant cancer cells. Furthermore, oncometabolites contribute induction of EMT. IDH1/2 mutations that induce the accumulation of 2-HG lead to EMT by ZEB1 upregulation and miR-200 downregulation in breast tumors and in colorectal cancer cells. The high levels of D-2-HG positively regulate the expression of ZEB1 in colorectal cancer cell, thereby inducing EMT. (3) Glutamine metabolism has been shown to downregulate p53 levels. Glutamine metabolism inhibition increases p53 expression and then induces the p53-dependent upregulation of Snail-targeting microRNAs, thereby leading to EMT induction by decreasing Snail mRNA levels. In addition, the abnormal TCA cycle enzymes, such as IDH mutants, prevent p53 activities. (4) Mutations of IDH, SDH, and FH induce ROS production. ROS play an important role in EMT. IDH mutation inhibits the production of NADPH and increases the consumption of NADPH. FH mutation also decreases NADPH levels by accumulation of fumarate. NADPH homeostasis plays an important role in the survival of cancer cells.