Testis-specific Y-like 5 (TSPYL5) has been postulated to be a tumor suppressor gene, and its hypermethylation is often associated with human disease, especially cancer.

TSPYL5 is a suppressor of p53 function through its interaction with USP7 (Epping MT, etal, Nat Cell Biol, Jan 2011;13(1):102-8; http://www.ncbi.nlm.nih.gov/pubmed/21170034 ).

TSPYL5 is one of the prognosis genes in Agendia's MammaPrint breast cancer test (see Agendia profile in the Company module).

TSPYL5 is frequently amplified in breast cancer. Investigators at the Netherlands Cancer Institute, in Amsterdam, and at Beth Israel Deaconess Cancer Center, Harvard Medical School (Boston, MA), report that high TSPYL5 expression is an independent marker of poor outcome in breast cancer. TSPYL5 interacts with ubiquitin-specific protease 7 (USP7), also known as herpesvirus-associated ubiquitin-specific protease (HAUSP). USP7 is the deubiquitylase for p53. TSPYL5 reduces the activity of USP7 resulting in increased p53 ubiquitylation. Thus, TSPYL5 reduces p53 protein levels and inhibits activation of p53-target genes. Furthermore, expression of TSPYL5 overrides p53-dependent proliferation arrest and oncogene-induced senescence, and contributes to oncogenic transformation in multiple cell-based assays. Therefore, TSPYL5 as a suppressor of p53 function through its interaction with USP7 (Epping MT, etal, Nat Cell Biol, Jan 2011;13(1):102-8; http://www.ncbi.nlm.nih.gov/pubmed/21170034 ).

Gene silencing of TSPYL5 is mediated by aberrant promoter methylation in gastric cancer. Investigators at the Cancer Research Institute, National University College of Medicine (Seoul, South Korea) report that TSPYL5 is inactivated by DNA methylation and could be a putative epigenetic target gene in gastric cancer. The expression of TSPYL5 mRNA was frequently downregulated and inversely correlated with DNA methylation in 7/9 gastric cancer cell lines. TSPYL5 mRNA expression was restored after treatment with a DNA methyltransferase inhibitor. Hypermethylation at the CpG islands of TSPYL5 was detectable at a high frequency in 23 of 36 (63.9%) primary gastric tumors. Furthermore, TSPYL5 suppressed the growth of gastric cancer cells. There is, therefore, a strong association between TSPYL5 expression and hypermethylation, and aberrant methylation at a CpG island of TSPYL5 may play an important role in the development of gastric cancer (Jung Y, etal, Lab Invest, Feb 2008;88(2):153-60; http://www.ncbi.nlm.nih.gov/pubmed/18059362 ).

TSPYL5 is involved in cell growth and resistance to radiation in A549 cells via the regulation of the p21(WAF1/Cip1) and PTEN/AKT pathway. Investigators at the Korea Atomic Energy Research Institute report that the TSPYL5 gene was less methylated (30%) in A549 lung adenocarcinoma cells, which are relatively resistant to gamma radiation, than in H460 lung cancer cells, in which the TSPYL5 gene was hypermethylated in 95% of cases; thus, the expression level of TSPYL5 is much higher in A549 cells than in H460 cells. TSPYL5 suppression with silencing RNA in A549 cells upregulated cellular PTEN, followed by downregulation of AKT activation. Therefore, blockage of TSPYL5 sensitized A549 cells to cytotoxic treatment such as gamma radiation. In addition, TSPYL5 suppression increased the level of p21(WAF1/Cip1) and subsequently induced inhibition of cell growth in A549 cells. The overexpression of TSPYL5 in H460 cells had the opposite effects. Therefore, TSPYL5 modulates cell growth and sensitizes tumor cells to the detrimental effects of radiation (Kim EJ, etal, Biochem Biophys Res Commun, 12 Feb 2010;392(3):448-53; http://www.ncbi.nlm.nih.gov/pubmed/20079711 ).

TSPYL5 is often silenced by aberrant DNA methylation in malignant glioma. Investigators at the University of Florida College of Medicine (Gainesville, FL) identified >160 genes upregulated by 5-aza-2'-deoxycytidine and trichostatin A treatment in malignant glioma cells. Further characterization revealed that 10 of these genes, including the putative metastasis suppressor CST6, the apoptosis-inducer BIK, and TSPYL5, whose function is unknown, were frequent targets of epigenetic silencing in glioma cell lines and primary tumors and suppressed glioma cell growth in culture. Furthermore, other members of the TSPYL gene family are epigenetically silenced in glioma. These studies, therefore, lay the foundation for a comprehensive understanding of the full extent of epigenetic changes in glioma and how they may be exploited for therapeutic purposes (Kim TY, etal, Cancer Res, 1 Aug 2006;66(15):7490-501; http://www.ncbi.nlm.nih.gov/pubmed/16885346 ).