Role of the Histone demethylase JARID1d in Epigenetic Events of Prostate Cancer

描述（由申请人提供）：除了遗传改变外，表观遗传改变-基因表达或细胞表型的可遗传改变而没有DNA改变-是前列腺癌事件的主要驱动力。与我们对遗传改变的理解取得巨大进展相比，表观遗传变化的分子基础仍有待进一步探索。组蛋白赖氨酸(K)甲基化已成为与基因表达表观遗传调控相关的标志。特别是，组蛋白H3赖氨酸4的三甲基化（trimethyl H3K4）是一个全基因组的表观遗传信号，占据并影响所有基因调控区域的75%。这一关键表观遗传信号的全局和局部改变通常发生在许多晚期前列腺肿瘤中，并与癌基因激活和肿瘤抑制基因失活有关。然而，尚不清楚三甲基H3K4谱的这种改变是如何在前列腺癌细胞中发生的。这项拟议研究的长期目标是表征晚期前列腺癌中与三甲基H3K4谱改变相关的表观遗传事件的分子机制。在最近的一项突破性研究中，我们发现JARID1d是一种新型的“男性特异性”组蛋白去甲基酶，能够从三甲基和二甲基H3K4中“去除甲基”（去甲基化）（Cell, 2007）。此外，我们的生物信息学分析显示JARID1d水平在晚期前列腺肿瘤中失调，表明JARID1d在前列腺癌事件中涉及三甲基H3K4改变的表观遗传变化中起重要作用。我们的初步研究发现了新的JARID1d相关蛋白，这些蛋白可能参与了JARID1d的募集和分子调控。基于这些令人兴奋的、明确的发现，我们的中心假设是JARID1d的失调在JARID1d靶基因的三甲基H3K4谱的表观遗传改变中起关键作用，从而导致前列腺癌的发生。在本研究中，我们重点了解JARID1d在前列腺癌事件中与三甲基H3K4改变相关的表观遗传变化中的作用和调控。具体目的是：1)确定JARID1d的染色质位置和募集机制；2)阐明调控jarid1d介导的去甲基化的分子机制；3)确定JARID1d在前列腺肿瘤进展和转移中的作用。我们提出的研究是理解晚期前列腺肿瘤中常见表观遗传事件（即三甲基H3K4谱的改变）的分子机制的基础，并将揭示表观遗传修饰子JARID1d在前列腺肿瘤进展和侵袭中的前所未有的作用。

DESCRIPTION (provided by applicant): 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.