Ubiquitin C-Terminal Hydrolase L1 in Tumorigenesis

Figure 2

The potential roles of UCH-L1 in tumorigenesis. (a) UCH-L1 as a possible oncogene that promotes metastasis and cell growth. (1) UCH-L1 is up-regulated in several tumor tissues and cancer cell lines [7–13]. (2) Elevated UCH-L1 may stimulate Akt through inhibition of the phosphatase PHLLP1 [11], leading to increased MAPK signaling [8]. (3) UCH-L1 has been reported to decrease polyubiquitination and proteasomal degradation of β-catenin, resulting in enhanced β-catenin-mediated transcription [30]. (4) Increased β-catenin and Akt signaling could potentially cause changes in gene transcription that promote metastasis and proliferation and inhibit apoptosis, resulting in enhanced oncogenicity [31–33]. (5) UCH-L1 binds to JAB1 and promotes the nuclear export and subsequent proteasomal degradation of the cell cycle inhibitor p27 [13]. (6) Upregulation of UCH-L1 has been reported to promote proteasomal degradation of p53 [11], which may be a consequence of activation of Akt signaling. Reduction of p27 and p53 levels by UCH-L1 may attenuate cell cycle arrest, allowing for uncontrolled cell growth. (b) UCH-L1 as a putative tumor suppressor in certain cancer subtypes. (1) Reduction of UCH-L1 transcription via promoter methylation-silencing has been observed in certain cancer cells and tumor tissues (e.g., nasopharyngeal carcinomas [10] and gastric cancer cells [34]). (2) In these cancer types, it has been proposed that UCH-L1 promotes deubiquitination of p53 and inhibits its proteasomal degradation [10, 16]. Reduced UCH-L1 transcription due to promoter methylation may thus lead to increased degradation of p53, resulting in a reduction of p53-mediated transcription of tumor suppressing genes and enhanced tumorigenesis (see text for more details).