TRIM28 fuels prostate cancer growth through SETDB1-mediated epigenetic silencing of androgen metabolic genes UGT2B15 and UGT2B17

TRIM28通过SETDB1介导的雄激素代谢基因UGT2B15和UGT2B17的表观遗传沉默促进前列腺癌的生长

基本信息

批准号：
10573177
负责人：
Ka wing Fong
金额：
$ 32.63万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-03-01 至 2026-12-31
项目状态：
未结题

项目摘要

Prostate cancer (PCa) is the second-leading cause of cancer-related death in men. The mainstay treatment for metastatic PCa is androgen deprivation therapy (ADT). However, the disease will inevitably return in an incurable form termed castration-resistant prostate cancer (CRPC). Importantly, aberrant androgen receptor (AR) activation in the milieu of low androgen is the main driver of CRPC. Molecular characterization of CRPC paves the way for discovery of novel therapeutic targets, and my previous studies showed that TRIM28 is aberrantly upregulated in advanced PCa. High TRIM28 levels are associated with worse clinical outcomes, which suggests that TRIM28 could serve as a promising target for PCa therapy. It is known that TRIM28 in a complex with trimethyl-histone H3 lysine 9 (H3K9me3)-specific methyltransferase (SETDB1) possesses transcriptional co-repressor activity but its genomic targets remain largely unexplored in PCa. Moreover, the TRIM28 downstream oncogenic pathway has not been comprehensively investigated in PCa. By molecular gene signature analysis, I found that the steroid hormone metabolic pathway is regulated by TRIM28. In particular, I found that the androgen eliminating enzymes UGT2B15 and UGT2B17 are the key TRIM28-repressed genes. It is known that genomic targeting of the TRIM28 complex is facilitated by transcription factors that bind to specific DNA recognition motifs. My data revealed that TRIM28 interacts with AR. In addition, my preliminary results indicated there is co-occupancy of TRIM28, AR and H3K9me3 deposition at UGT2B15 and UGT2B17 gene loci. Based on these findings, I hypothesize that TRIM28 acts together with AR to epigenetically silence the expression of androgen metabolic enzymes through SETDB1-mediated H3K9me3. I propose to test this hypothesis in Aim1. UGT2B15 and UGT2B17 are known to inactivate androgen through glucuronidation using UDPGlucA as the sugar-donor. Given that the overexpression of UGT2B15 and UGT2B17 correlate to more UDP-GlucA consumption, I hypothesize that levels of UDP-GlucA will decrease in TRIM28 knockdown cells or with treatment of the SETDB1 inhibitor, Mit, in CRPC cells. I propose to test this hypothesis in Aim2. The results from this proposal will not only reveal a novel epigenetic mechanism for regulating androgen glucuronidation, but also have significant implications for the development of SETDB1-targeted therapy for CRPC treatment.

前列腺癌（PCA）是男性与癌症相关死亡的第二大原因。转移性PCA的主要治疗方法是雄激素剥夺疗法（ADT）。然而，该疾病将不可避免地以无法治愈的形式恢复为持cast割的前列腺癌（CRPC）。重要的是，低雄激素环境中的异常雄激素受体（AR）激活是CRPC的主要驱动力。 CRPC的分子表征为发现新型治疗靶标的发现铺平了道路，而我以前的研究表明，TRIM28在晚期PCA中异常上调。高TRIM28水平与较差的临床结果有关，这表明TRIM28可以成为PCA治疗的有希望的靶标。众所周知，在具有三甲基荷兰H3赖氨酸9（H3K9ME3）特异性甲基转移酶（SETDB1）的复合物中TRIM28具有转录共抑制活性，但其基因组靶标在PCA中仍未探索。此外，在PCA中尚未对TRIM28下游致癌途径进行全面研究。通过分子基因特征分析，我发现类固醇激素代谢途径受TRIM28的调节。特别是，我发现消除酶UGT2B15和UGT2B17的雄激素是密钥TRIM28抑制基因。众所周知，TRIM28复合物的基因组靶向是由与特定DNA识别基序结合的转录因子促进的。我的数据显示TRIM28与AR相互作用。此外，我的初步结果表明，在UGT2B15和UGT2B17基因基因座的TRIM28，AR和H3K9me3沉积的共占者。基于这些发现，我假设TRIM28与AR一起起作用，表观遗传学在二下，通过SETDB1介导的H3K9me3沉默了雄激素代谢酶的表达。我建议在AIM1中检验这一假设。已知UGT2B15和UGT2B17通过使用udpgluca作为糖含量来使雄激素通过葡萄糖醛酸化灭活。鉴于UGT2B15和UGT2B17的过表达与更多的UDP-Gluca消耗相关，因此我假设在TRIM28敲低细胞中，UDP-Gluca的水平将降低，或者与SETDB1抑制剂MIT，MIT，MIT，MIT，CRPC细胞中的处理水平降低。我建议在AIM2中检验这一假设。该提案的结果不仅会揭示一种调节雄激素葡萄糖醛酸化的新型表观遗传机制，而且对SETDB1靶向治疗的CRPC治疗的发展具有重要意义。