Research Summary

My laboratory is interested in understanding the roles of the Y chromosome genes and their X homologues in human development, physiology and diseases. Current interests focus on identifying the roles of sex chromosome genes in human cancers, particularly on prostate cancer, testicular germ cell tumors, and liver cancer; and in sexual dimorphic diseases, such as neurological disorders and cardiovascular disease. Various advanced genetic, genomic, proteomic, and transgenic mouse strategies are used in our research.

There are three categories of genes on the human Y chromosome: 1) those on the pseudoautosomal regions (PARs) which have identical homologues on the X chromosome; 2) those on the male-specific region on the Y chromosome (MSY), which have highly conserved homologues on the X chromosome and expressed widely in various tissues; and 3) those on the MSY, relatively diverged from their X homologues and specifically expressed in the testis. The first two categories of Y chromosome genes and their X homologues likely serve dosage-dependent and essential functions. Mosaic loss of the entire Y chromosome or inactivation of PAR and highly conserved MSY genes could result in dosage deficiency and disease predisposition. On the other hand, aberrant expression of Y-located and testis-specific genes in somatic tissues could exert male-specific effects on normal development, physiology and disease pathogeneses. Collectively such abnormalities could contribute genetically to various aspects of sex differences between males and females. Our research focuses on the ectopic activation of Y-linked genes, such as the sex-determining SRY gene and the spermatogonia factor TSPY, in male-biased diseases, including neurological disorders, cardiovascular disease, non-alcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma.

One major project focuses on the contrasting roles of the Y-located TSPY gene and its X homologue TSPX in various cancers and sex hormone-associated functions/diseases. TSPY is the gene for the gonadoblastoma locus on the Y chromosome (GBY), the only oncogenic locus on the male-specific chromosome. It serves normal functions as a spermatogenic factor. When aberrantly activated in incompatible cells, it behaves as an oncogene and promotes cell proliferation by stimulating the cyclin B-CDK1 phosphorylation activities, important for G2/M transition in the cell cycle. Significantly, TSPX, possesses contrasting property in suppressing the cyclin B-CDK1 activities, and maintaining the orderly G2/M transition and checkpoint integrity. Hence it is an X-linked tumor suppressor gene. Accordingly, aberrant activation of the Y-located TSPY oncogene and/or inactivation of the X-located TSPX tumor suppressor could collectively predispose males to oncogenesis. Importantly, both TSPY and TSPX could interact with the male sex hormone receptor, androgen receptor (AR) and its constitutively active variants, such as AR-V7. TSPY exacerbates and TSPX represses the transactivation of AR and AR-V7 functions in ligand-dependent and independent manners respectively. Further, TSPY is regulated by androgen via direct binding of AR and AR-V7 on its promoter, thereby supporting the notion that the male-specific oncogene TSPY and the male sex hormone receptors form a positive feedback loop in the oncogenesis of various male-specific and/or male-biased cancers and amplify synergistically their oncogenic actions. Since androgen, AR and AR-V7 play key roles in prostatic oncogenesis and advances to castration resistant prostate cancer (CRPC) and the lethal neuroendocrine prostate cancer, the differential actions of TSPY and TSPX on AR and AR-V7 suggest that they are important modulators for such lethal evolution of this important cancer in men. Our research in this project is designed to understand the molecular mechanisms of TSPY and TSPX actions and their translational applications for diagnosis, prognosis and treatments on male sex hormone-associated cancers, such prostate cancer and hepatocellular carcinoma.

Research Funding

  • October 1, 2019 - September 30, 2024 - Research Career Scientist Award, Principal Investigator. Sponsor: Department of Veterans Affairs, Sponsor Award ID: 1IK6BX004854
  • July 1, 2019 - June 30, 2024 - Molecular Mechanisms of a Male-Specific Positive Feedback Loop in Liver Cancer, Principal Investigator. Sponsor: Department of Veterans Affairs, Sponsor Award ID: 1IO1BX004446
  • September 1, 2019 - September 30, 2020 - Single-Cell Next-Generation Sequencing Library Preparation System, Principal Investigator. Sponsor: Department of Veterans Affairs, Sponsor Award ID: 1IS1BX005014-01
  • April 1, 1994 - September 30, 2019 - RESEARCH CAREER SCIENTIST AWARD, PRINCIPAL INVESTIGATOR. Sponsor: VA, Sponsor Award ID: RESEARCH CAREER SCIENTIST

Education

Harpur College, Binghamton University, B.A., 1973, Chemistry
MD Anderson Cancer Center-UTHealth, M.S., 1976, Cell Biology
MD Anderson Cancer Center-UTHealth, Ph.D., 1979, Genetics
University of California, San Francisco, Postdoctoral Fellowship,1979-1984, Human Genetics

Honors & Awards

  • 1973-76
    Robert A. Welch Predoctoral Fellowship, Graduate School of Biomedical Sciences, MD Anderson Cancer Center UTHealth, Houston
  • 1976-79
    Rosalie B. Hite Predoctoral Fellowship, Graduate School of Biomedical Sciences, MD Anderson Cancer Center UTHealth, Houston
  • 1975-77
    Merit Awards, Excellent Student Research, Graduate School of Biomedical Sciences, MD Anderson Cancer Center UTHealth, Houston
  • 1979-82
    A. P. Giannini Postdoctoral Fellowship, University of California, San Francisco

Selected Publications

  1. Lau YC. Y chromosome in health and diseases. Cell Biosci. 2020; 10:97.  View on PubMed
  2. Kido T, Tabatabai ZL, Chen X, Lau YC. Potential dual functional roles of the Y-linked RBMY in hepatocarcinogenesis. Cancer Sci. 2020 Aug; 111(8):2987-2999.  View on PubMed
  3. Lau YC, Li Y, Kido T. Battle of the sexes: contrasting roles of testis-specific protein Y-encoded (TSPY) and TSPX in human oncogenesis. Asian J Androl. 2019 May-Jun; 21(3):260-269.  View on PubMed
  4. Vogt PH, Besikoglu B, Bettendorf M, Frank-Herrmann P, Zimmer J, Bender U, Knauer-Fischer S, Choukair D, Sinn P, Lau YC, Heidemann PH, Strowitzki T. Gonadoblastoma Y locus genes expressed in germ cells of individuals with dysgenetic gonads and a Y chromosome in their karyotypes include DDX3Y and TSPY. Hum Reprod. 2019 04 01; 34(4):770-779.  View on PubMed
  5. Kido T, Lau YC. The Y-linked proto-oncogene TSPY contributes to poor prognosis of the male hepatocellular carcinoma patients by promoting the pro-oncogenic and suppressing the anti-oncogenic gene expression. Cell Biosci. 2019; 9:22.  View on PubMed
  6. Kido T, Li Y, Tanaka Y, Dahiya R, Chris Lau YF. The X-linked tumor suppressor TSPX downregulates cancer-drivers/oncogenes in prostate cancer in a C-terminal acidic domain dependent manner. Oncotarget. 2019 Feb 19; 10(15):1491-1506.  View on PubMed
  7. Kido T, Sun Z, Lau YC. Aberrant activation of the human sex-determining gene in early embryonic development results in postnatal growth retardation and lethality in mice. Sci Rep. 2017 06 23; 7(1):4113.  View on PubMed
  8. Li Y, Zhang DJ, Qiu Y, Kido T, Lau YC. 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. 2017 03 01; 26(5):901-912.  View on PubMed
  9. Kido T, Lau YC. Identification of a TSPY co-expression network associated with DNA hypomethylation and tumor gene expression in somatic cancers. J Genet Genomics. 2016 10 20; 43(10):577-585.  View on PubMed
  10. Fukuhara S, Chang I, Mitsui Y, Chiyomaru T, Yamamura S, Majid S, Saini S, Deng G, Gill A, Wong DK, Shiina H, Nonomura N, Lau YF, Dahiya R, Tanaka Y. Functional role of DNA mismatch repair gene PMS2 in prostate cancer cells. Oncotarget. 2015 Jun 30; 6(18):16341-51.  View on PubMed
  11. Kido T, Lau YF. Roles of the Y chromosome genes in human cancers. Asian J Androl. 2015 May-Jun; 17(3):373-80.  View on PubMed
  12. Li Y, Kido T, Garcia-Barcelo MM, Tam PK, Tabatabai ZL, Lau YF. 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. 2015 Feb 01; 24(3):685-97.  View on PubMed
  13. Li Y, Zheng M, Lau YF. The sex-determining factors SRY and SOX9 regulate similar target genes and promote testis cord formation during testicular differentiation. Cell Rep. 2014 Aug 07; 8(3):723-33.  View on PubMed
  14. Kido T, Lo RC, Li Y, Lee J, Tabatabai ZL, Ng IO, Lau YF. The potential contributions of a Y-located protooncogene and its X homologue in sexual dimorphisms in hepatocellular carcinoma. Hum Pathol. 2014 Sep; 45(9):1847-58.  View on PubMed
  15. Kido T, Lau YF. The Y-located gonadoblastoma gene TSPY amplifies its own expression through a positive feedback loop in prostate cancer cells. Biochem Biophys Res Commun. 2014 Mar 28; 446(1):206-11.  View on PubMed
  16. Kido T, Schubert S, Hatakeyama S, Ohyama C, Schmidtke J, Lau YF. Expression of a Y-located human proto-oncogene TSPY in a transgenic mouse model of prostate cancer. Cell Biosci. 2014 Feb 17; 4(1):9.  View on PubMed
  17. Zheng M, Li Y, Lau YF. Application of the simple and efficient Mpeak modeling in binding peak identification in ChIP-chip studies. Methods Mol Biol. 2013; 1067:185-202.  View on PubMed
  18. Li Y, Taketo T, Lau YF. Isolation of fetal gonads from embryos of timed-pregnant mice for morphological and molecular studies. Methods Mol Biol. 2012; 825:3-16.  View on PubMed
  19. Kido T, Ou JH, Lau YF. The X-linked tumor suppressor TSPX interacts and promotes degradation of the hepatitis B viral protein HBx via the proteasome pathway. PLoS One. 2011; 6(7):e22979.  View on PubMed
  20. Kido T, Schubert S, Schmidtke J, Chris Lau YF. Expression of the human TSPY gene in the brains of transgenic mice suggests a potential role of this Y chromosome gene in neural functions. J Genet Genomics. 2011 May 20; 38(5):181-91.  View on PubMed

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