The testis-specific protein Y-encoded (TSPY) gene is a tandemly repeated gene on the short arm of the human Y chromosome. Its 2.8-kb structural gene is embedded within a 20-kb highly homologous unit that is tandemly repeated up to 64 times, constituting the largest tandem array of functional sequences in the human genome. The TSPY repeats are hot spots for both genomic instability and epigenetic dysregulation on the Y chromosome. TSPY is the proto-oncogene for the gonadoblastoma locus on the Y chromosome (GBY), the only oncogenic locus on this male-specific chromosome. Our research shows that TSPY harbors a conserved protein interacting domain, termed SET/NAP. TSPX is a single-copy TSPY homologue on the X chromosome. Both TSPY and TSPX share significant homologies at both gene organization and protein structure. When ectopically expressed, TSPY and TSPX show contrasting properties in cell cycle regulation. TSPY is ectopically expressed and plays key roles in the initiation and/or progression of gonadoblastoma, testicular germ cell tumors, prostate cancer, and sexual dimorphic cancers, such as hepatocellular carcinoma. TSPY potentiates cell proliferation, accelerates the transition and disrupts the G2/M checkpoints, binds cyclin B and enhances cyclin B-CDK1 kinase activities, and promotes tumor growth in athymic mice. TSPY induces gonadoblastoma-like structure in the ovaries of transgenic mice. TSPX is a tumor suppressor. It binds cyclin B, but represses the cyclin B-CDK1 kinase activity. Ectopic expression of TSPX arrests cells at G2/M stage, and represses tumor growth in athymic mice. We postulate that TSPX serve a normal function in maintaining an orderly cell proliferation and growth while TSPY, when ectopically expressed, counteracts such function(s) and promotes tumorigenesis in susceptible cells. Recently, we have showed that TSPY interacts with androgen receptor (AR) and exacerbates its ligand-dependent transactivation of responsive genes while TSPX interacts but represses AR functions. Hence, TSPY and TSPX could participate in the transcriptional programs mediated by androgen-dependent prostatic oncogenesis. When a TSPY transgene is introduced into the transgenic mouse (LADY) model of prostate cancer, it is ectopically activated at the onset of prostatic oncogenesis in the bi-transgenic mice, resulting in qualitatively more nodular tumors than those from animals without TSPY. These results have provided some important clues and excellent resources for investigating the mechanisms by which TSPY could contribute to prostatic oncogenesis. We will study these problems under three specific aims. First, we plan to elucidate the epigenetic changes associated with TSPY transgene activation during prostatic oncogenesis in the TSPY-LADY bi-transgenic mice, in terms of tumor pathogenesis, transgene expression, DNA methylation status of the TSPY promoter and exon 1, and identification of transcription factors and repressors affected by such epigenetic changes. Second, we will determine the domains responsible for the contrasting functions of TSPY and TSPX on AR transactivation and elucidate the structure-function relationship with a prostatic tissue recombination strategy. Third, we plan to identify and confirm the target genes of a TSPY-AR transcription complex using advanced chromatin immunoprecipitation and promoter tiling microarray (ChIP-Chip) approach. We will determine the transcriptomes of tumors from TSPY-LADY and LADY transgenic mice under normal and hormone-ablated conditions, thereby deducing the genes and pathways mostly affected by an ectopically expressed TSPY transgene in prostatic oncogenesis. We will characterize in details those differentially expressed genes whose promoters are also bound by a TSPY-AR transcriptional complex. The proposed research will provide critical insights on the roles of TSPY and TSPX on prostatic oncogenesis, and translational opportunities in developing diagnostic biomarkers and targets for therapeutic strategies for prostate cancer.

Public Health Relevance

Prostate cancer is a prevalent cancer among our veterans. The etiology of this man-only cancer is uncertain. For the past few years, we have examined the functions of a gene on the male-specific chromosome (i.e. Y chromosome) and showed that it contains an oncogene that could promote tumor development in various cancers, including prostate cancer. It has a similar (homologous) gene on the X chromosome that has opposite functions against those of the Y-located oncogene. Hence, the X-gene is a tumor suppressor gene. We show that these two sex chromosome genes can affect testosterone (male-hormone) associated physiology, again in opposing directions. Since testosterone is very important for prostate cancer development and progression, we propose to examine the differences of these two sex chromosome genes in an animal model of prostate cancer. This project will shed important insights on how the Y-oncogene and X-tumor suppressor operate and how one can interfere or boost their actions respectively to treat prostate cancer.

National Institute of Health (NIH)
Veterans Affairs (VA)
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Oncology A (ONCA)
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Veterans Affairs Medical Center San Francisco
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Kido, Tatsuo; Sun, Zhaoyu; Lau, Yun-Fai Chris (2017) Aberrant activation of the human sex-determining gene in early embryonic development results in postnatal growth retardation and lethality in mice. Sci Rep 7:4113
Li, Yunmin; Zhang, Dong Ji; Qiu, Yun et al. (2017) The Y-located proto-oncogene TSPY exacerbates and its X-homologue TSPX inhibits transactivation functions of androgen receptor and its constitutively active variants. Hum Mol Genet 26:901-912
Kido, Tatsuo; Lau, Yun-Fai Chris (2016) Identification of a TSPY co-expression network associated with DNA hypomethylation and tumor gene expression in somatic cancers. J Genet Genomics 43:577-585
Li, Yunmin; Kido, Tatsuo; Garcia-Barcelo, Maria M et al. (2015) SRY interference of normal regulation of the RET gene suggests a potential role of the Y-chromosome gene in sexual dimorphism in Hirschsprung disease. Hum Mol Genet 24:685-97
Kido, Tatsuo; Lau, Yun-Fai Chris (2015) Roles of the Y chromosome genes in human cancers. Asian J Androl 17:373-80
Li, Yunmin; Zheng, Ming; Lau, Yun-Fai Chris (2014) The sex-determining factors SRY and SOX9 regulate similar target genes and promote testis cord formation during testicular differentiation. Cell Rep 8:723-33
Kido, Tatsuo; Lo, Regina Cheuk-Lam; Li, Yunmin et al. (2014) The potential contributions of a Y-located protooncogene and its X homologue in sexual dimorphisms in hepatocellular carcinoma. Hum Pathol 45:1847-58
Kido, Tatsuo; Lau, Yun-Fai Chris (2014) The Y-located gonadoblastoma gene TSPY amplifies its own expression through a positive feedback loop in prostate cancer cells. Biochem Biophys Res Commun 446:206-11
Kido, Tatsuo; Schubert, Stephanie; Hatakeyama, Shingo et al. (2014) Expression of a Y-located human proto-oncogene TSPY in a transgenic mouse model of prostate cancer. Cell Biosci 4:9
Zheng, Ming; Li, Yunmin; Lau, Yun-Fai Chris (2013) Application of the simple and efficient Mpeak modeling in binding peak identification in ChIP-chip studies. Methods Mol Biol 1067:185-202

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