In addition to genetic alterations, epigenetic changes- heritable changes in gene expression or cellular phenotypes without DNA alterations - are a major driving force for prostate cancer events. In contrast to great advance in our understanding of genetic alterations, the molecular basis underlying epigenetic changes remains to be further explored. Histone lysine (K) methylation has emerged as a hallmark associated with epigenetic regulation of gene expression. In particular, trimethylation at histone H3 lysine 4 (trimethyl H3K4) is a genome-wide epigenetic signal that occupies and affects 75% of all the gene-regulatory regions. Alterations in the global and local profile of this key epigenetic signal commonly occur in many advanced prostate tumors and are associated with oncogene activation and tumor suppressor gene inactivation. However, it is unknown how such alterations in trimethyl H3K4 profiles occur in prostate cancer cells. The long-term objective of the proposed study is to characterize the molecular mechanisms responsible for epigenetic events associated with alterations in trimethyl H3K4 profiles in advanced prostate cancer. In a recent breakthrough study, we identified JARID1d as a novel """"""""male-specific"""""""" histone demethylase that is capable of """"""""removing methyl groups"""""""" (demethylating) from trimethyl and dimethyl H3K4 (Cell, 2007). In addition, our bioinformatic analysis showed that JARID1d levels are dysregulated in advanced prostate tumors, indicating an importance role for JARID1d in epigenetic changes involving alterations in trimethyl H3K4 during prostate cancer events. Our preliminary studies identified novel JARID1d-associated proteins that are likely involved in the recruitment and the molecular regulation of JARID1d. Based on these exciting, definitive findings, our central hypothesis is that dysregulation of JARID1d plays a key role in epigenetic alterations in trimethyl H3K4 profiles at JARID1d target genes and consequently contributes to prostate cancer events. In the proposed study, we focus on understanding the role and regulation of JARID1d in epigenetic changes associated with trimethyl H3K4 alterations during prostate cancer events.
Specific Aims are to 1) Determine the chromatin locations and recruitment mechanisms of JARID1d;2) Elucidate the molecular mechanisms that regulate JARID1d-mediated demethylation;3) Determine the role of JARID1d in prostate tumor progression and metastasis. Our proposed studies are fundamental to understanding the molecular mechanisms underlying a common epigenetic event, i.e., alterations in trimethyl H3K4 profiles, in advanced prostate tumors and will uncover an unprecedented role for the epigenetic modifier JARID1d in prostate tumor progression and invasion.
The studies proposed here are aimed at understanding the role of the recently identified histone demethylase JARID1d in epigenetic events associated with alterations in trimethyl H3K4 profiles that commonly occur during prostate cancer progression and metastasis. These studies promise to provide novel insights into the molecular mechanisms underlying such epigenetic events that occur in advanced prostate cancer. Accomplishing our goal is highly relevant to the screening and development of novel therapeutic agents to inhibit proliferation and metastasis of advanced prostate tumors via the modulation of JARID1d's functions.
|Li, Na; Li, Yuanyuan; Lv, Jie et al. (2016) ZMYND8 Reads the Dual Histone Mark H3K4me1-H3K14ac to Antagonize the Expression of Metastasis-Linked Genes. Mol Cell 63:470-84|
|Dhar, Shilpa S; Lee, Sung-Hun; Chen, Kaifu et al. (2016) An essential role for UTX in resolution and activation of bivalent promoters. Nucleic Acids Res 44:3659-74|
|Lee, Sung-Hun; Chen, Tsai-Yu; Dhar, Shilpa S et al. (2016) A feedback loop comprising PRMT7 and miR-24-2 interplays with Oct4, Nanog, Klf4 and c-Myc to regulate stemness. Nucleic Acids Res 44:10603-10618|
|Li, Na; Dhar, Shilpa S; Chen, Tsai-Yu et al. (2016) JARID1D Is a Suppressor and Prognostic Marker of Prostate Cancer Invasion and Metastasis. Cancer Res 76:831-43|
|Alam, Hunain; Gu, Bingnan; Lee, Min Gyu (2015) Histone methylation modifiers in cellular signaling pathways. Cell Mol Life Sci 72:4577-92|
|Kim, Jae-Hwan; Sharma, Amrish; Dhar, Shilpa S et al. (2014) UTX and MLL4 coordinately regulate transcriptional programs for cell proliferation and invasiveness in breast cancer cells. Cancer Res 74:1705-17|
|Dhar, Shilpa S; Alam, Hunain; Li, Na et al. (2014) Transcriptional repression of histone deacetylase 3 by the histone demethylase KDM2A is coupled to tumorigenicity of lung cancer cells. J Biol Chem 289:7483-96|
|Gu, Bingnan; Lee, Min Gyu (2013) Histone H3 lysine 4 methyltransferases and demethylases in self-renewal and differentiation of stem cells. Cell Biosci 3:39|
|Wagner, Klaus W; Alam, Hunain; Dhar, Shilpa S et al. (2013) KDM2A promotes lung tumorigenesis by epigenetically enhancing ERK1/2 signaling. J Clin Invest 123:5231-46|
|Dhar, Shilpa S; Lee, Sung-Hun; Kan, Pu-Yeh et al. (2012) Trans-tail regulation of MLL4-catalyzed H3K4 methylation by H4R3 symmetric dimethylation is mediated by a tandem PHD of MLL4. Genes Dev 26:2749-62|