Role of the Y-Located TSPY Gene in Human Oncogenesis

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DESCRIPTION (provided by applicant): 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.