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Histone H2A Ubiquitination in Inflammation and Cancer.

Wenlai Zhou

Appointment Period: 2007-2008 / Grant Year: [23]

Wenlai ZhouProstate cancer is one of the leading causes of cancer related deaths among men in the United States. Resistance to selective androgen receptor modulators, drugs used for the treatment of patients with prostate tumors, has been postulated to reflect diverse mechanisms such as silencing/overexpression of the AR gene or mutations in the sequence, alterations of levels of nuclear receptor coregulators, altered expression of oncogenes/tumor suppressor genes or faulty activation of certain phosphorylation pathways. In many cases, dysregulation of AR-dependent transcription appeared to be the key to development of hormone resistance. Regulation of AR-dependent transcription in normal prostate and prostate cancer involves a number of coregulator complexes containing multiple histone-modifying enzymes, including acetylase/deacetylase and methylase/demethylase, e.g. recently discovered LSD1 and JMJD1A. Histone modifications, for instance acetylation, methylation, phosphorylation and ubiquitination, are believed to play central roles in chromatin remodeling, and transcriptional regulation and histone modification marks were reported to be valuable markers for prognosis of prostate cancer patients. Therefore, it is hypothesized that specific histone ubiquitination and corresponding enzymes are crucial in the progression of prostate cancer.

I have identified a H2A deubiquitinase, 2A-DUB (KIAA1915/MYSM1), which is required for the activation of several transcriptional events, including androgen receptor (AR)-regulated target gene in prostate cancer cells. Interestingly, the levels of 2A-DUB (KIAA1915/MYSM1) are significantly increased in hormone-resistant prostate cancer cells as compared with hormone-sensitive prostate cancer cells. In correlation, the levels of ubH2A are dramatically decreased in prostate tumors, serving as a cancer-related mark, in addition to other important histone modification marks that provide insights into prognosis. Secondly, I have identified a novel histone modifier, H2A ubiquitin ligase (2A-HUB), and elucidated that 2A-HUB functions as a combinatoric component of the N-CoR/HDAC1/3 repression machinery. Specifically, it is important in regulating a subset of chemokine genes and modulating macrophage response to TLR signaling.

These studies will provide information regarding the pathological roles of these gene mutations in human diseases. I believe that understanding the epigenetic regulation strategy in prostate carcinogenesis would have important insights for novel preventive and therapeutic approaches in prostate cancer, as the histone methy- and acetyltransferases are already linked to a variety of genetic disorders, and therefore have become targets for a disease treatment.

Lin L, Cui L, Zhou W, Dufort D, Zhang X, Cai CL, Bu L, Yang L, Martin J, Kemler R, Rosenfeld MG, Chen J, Evans SM. Beta-catenin directly regulates Islet1 expression in cardiovascular progenitors and is required for multiple aspects of cardiogenesis. Proc Natl Acad Sci USA. (2007) 104:9313-8. PMID: 17519333; PMCID: PMC1890491.

Zhu P, Zhou W, Wang J, Puc J, Ohgi KA, Erdjument-Bromage H, Tempst P, Glass CK, Rosenfeld MG. A histone H2A deubiquitinase complex coordinating histone acetylation and H1 dissociation in transcriptional regulation. Mol Cell. (2007) 27:609-21. PMID: 17707232; PMCID: PMC2709280.

Zhou W, Lin L, Majumdar A, Li X, Zhang X, Liu W, Etheridge L, Shi Y, Martin J, Van de Ven W, Kaartinen V, Wynshaw-Boris A, McMahon AP, Rosenfeld MG, Evans SM. Modulation of morphogenesis by noncanonical Wnt signaling requires ATF/CREB family-mediated transcriptional activation of TGFbeta2. Nat Genet. (2007) 39:1225-34. PMID: 17767158.

Zhou W, Zhu P, Wang J, Pascual G, Ohgi KA, Lozach J, Glass CK, Rosenfeld MG. Histone H2A monoubiquitination represses transcription by inhibiting RNA polymerase II transcriptional elongation. Mol Cell. (2008) 29:69-80. PMID: 18206970; PMCID: PMC2327256.

Zhou W, Wang X, Rosenfeld MG. Histone H2A ubiquitination in transcriptional regulation and DNA damage repair. Int J Biochem Cell Biol. (2009) 41:12-5. PMID: 18929679.