Abstract
Abstract Nuclear receptor-mediated regulation of gene expression, including estrogen-receptor-alpha (ERα), relies on a complex network of proteins that impose either repression or activation of gene expression. Among these, epigenetic “reader” proteins recognize combinatorial PTMs on histones, through distinct structure domains such as tandem plant homeodomains (PHD) and bromodomains (Bromo). We recently reported that tripartite motif-containing 24 (TRIM24), by means of its C-terminal tandem PHD finger and Bromo domains, recognizes unmethylated histone H3 lysine K4 (H3K4me0) and acetylated histone H3 lysine K23 (H3K23ac) within the same histone tail. In the presence of estrogen, dual chromatin reader TRIM24 preferentially recognizes these two histone marks, binds to ERα and regulates estrogen-dependent target genes. Depletion of TRIM24 inhibits breast cancer cell growth and enhances tamoxifen-induced growth inhibition. In addition, overexpression of TRIM24 correlates with decreased overall survival in breast cancer patients. We believe that TRIM24 can be a potential biomarker for breast cancer development, as well as a target for therapeutic treatment. The goal of my research is to target TRIM24 in breast cancer by identifying upstream epigenetic regulators that may influence TRIM24's function in ERα-regulated transcriptional activation. For TRIM24-regulated ERα target genes, estrogen stimulation results in a global loss of H3K4me2 at estrogen-responsive elements (EREs), where TRIM24 and ERα are recruited. Global binding profile of TRIM24 by ChIP-seq also shows that TRIM24 preferentially binds to regions depleted of H3K4me2, suggesting that upstream regulators may determine TRIM24 binding to chromatin. Demethylation of histones is mediated by specific enzymes called histone demethylases (HDMs). When we increase H3K4me2 at EREs by inhibiting the enzymatic activity of HDM, recruitment of both TRIM24 and ERα to target genes is diminished. As a result, activation of TRIM24-regulated estrogen-responsive genes is impaired. Previous work has suggested that the presence of threonine T6 phosphorylation on histone H3 (H3T6ph) prevents HDMs from demethylating H3K4me2. H3T6ph may therefore impose an inhibitory mark for LSD1-mediated demethylation of H3K4me2, and serves as an added layer of regulation for TRIM24 binding to histones, affecting subsequent function of TRIM24 as an ERα coactivator. These results may give insights into future therapeutic studies of targeting TRIM24 in breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3137. doi:1538-7445.AM2012-3137
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