Molecular basis of androgen receptor mediated gene transcriptional repression

雄激素受体介导的基因转录抑制的分子基础

• 批准号: 9062577
• 负责人: Changmeng Cai
• 金额: $ 24.62万
• 依托单位: UNIVERSITY OF MASSACHUSETTS BOSTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9062577
• 关键词: Affect; Androgen Receptor; Androgens; Binding; Binding Sites; Bioinformatics; CYP17A1 gene; Cancer Patient; Cell Cycle Progression; Cell Line; ChIP-seq; Chromatin; Clinical; Complex; DNA biosynthesis; Data; Development; Disease; ETV1 gene; Elements; Epigenetic Process; Feedback; Funding; Gene Amplification; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Genome; Goals; Grant; Health; Histones; Homeostasis; Introns; Israel; JUN gene; Lead; Ligands; Lysine; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Medical center; Mentors; Messenger RNA; Modification; Molecular; Pathway Analysis; Pathway interactions; Patients; Phase; Phosphorylation; Phosphotransferases; Physiological; Play; Prostate; Prostate Cancer therapy; Publishing; Receptor Activation; Receptor Gene; Receptor Signaling; Recruitment Activity; Regulation; Relapse; Repression; Research; Resistance; Resistance development; Role; Signal Transduction; Site; Source; Study models; Substrate Specificity; Synthetic Genes; TMPRSS2 gene; Transactivation; Transcription Repressor/Corepressor; Translating; United States National Institutes of Health; Universities; Work; Xenograft Model; base; cancer initiation; castration resistant prostate cancer; clinically relevant; cooperative study; deprivation; field study; fusion gene; gene repression; genome-wide; mRNA Expression; medical schools; next generation sequencing; novel; novel strategies; post-doctoral training; pre-doctoral; prevent; programs; prostate cancer cell; receptor binding; receptor expression; receptor function; transcription factor; transcriptome sequencing; tumor; tumor progression

DESCRIPTION (provided by applicant): In my pre-doctoral study, I worked with Dr. Lirim Shemshedini (University of Toledo) on studying gene regulation by androgen receptor (AR) in prostate cancer (PCa). I have published the results on studying the cooperative role of c-Jun on AR transactivation and the roles of AR regulated SGCα1, ETV1, and MRP4 genes in PCa. In my postdoctoral training, I joined Steven Balk lab at Beth Israel Deaconess Medical Center (BIDMC)/Harvard Medical School and focused on understanding roles of AR in the lethal form of PCa (CRPC) that develops the resistance to androgen deprivation therapy (ADT). Research in the Balk lab is focused on PCa and AR, and the lab has funding from multiple sources including NIH R01 support, a Prostate Cancer SPORE, DoD Prostate Cancer program, and PCF challenge grant. My initial study is on studying the crosstalk of AR and HER signaling and then I moved to the field of studying TMPRSS2:ERG fusion gene in PCa. Using fusion positive cell lines, I have established xenograft models that clearly mimic the progression of CRPC. Studying this model led to three major findings: (1) SOX9 was identified as the major downstream effector of TMPRSS2:ERG in fusion positive PCa; (2) increased intratumoal androgen synthesis mediates tumor resistance to ADT and CYP17A1 inhibition; (3) increased AR expression in CRPC is due to relieving AR suppression of its own gene. AR plays a pivotal role in primary PCa and regains its functions in CRPC. In contrast to the wellestablished AR activation function on gene transcription, its suppression function is poorly understood. This proposal mainly focuses on elucidating the molecular mechanisms of AR mediated gene transcriptional repression. My immediate goal of 2-yrs mentored phase will be to pursue the molecular basis and clinical relevance of AR mediated its own gene expression through binding of its intron 2 site (ARBS2) and repressing the gene transcription. Several other AR-repressed gene loci that mediate expression of androgen synthetic genes (HSD17B6 and AKR1C3) will also be studied. In particularly, the repressor complex on chromatin and their actions that results in the epigenetic modifications on ARBS2 and regulates its activity will be identified. More important, any distinct mechanism that separates AR as an activator versus a repressor needs to be elucidated. These findings will also be translated into clinical therapy to enhance the activity of ARBS2 but not affect AR activated gene loci. For the long-term goal, which includes the 3-yr independence phase, the findings on AR gene loci will be extended to the whole genome of PCa cells. Taking the advantages of next generation sequencing and bioinformatics analysis on high throughput data, the global AR-mediated suppressor elements will be identified in PCa cells and their functions will also be studied. Moreover, the global roles of AR interacted repressor complex on gene transcription and on prostate cancer initiation and progression will also be studied in the phase of proposal. Current findings clearly demonstrate that we do not yet fully understand how AR functions, and that further novel mechanisms of action may contribute to its regulation of subsets of genes. As AR regulates a large number of genes involved in many cellular pathways, the potential ability to selectively target subsets of these genes has broad implications for the therapy of PCa and other diseases.

描述(由申请人提供)： 在我的博士前研究中，我与Lirim Shemshedini博士(托莱多大学)合作研究基因 雄激素受体(AR)对前列腺癌(PCa)的调节作用我已经发表了关于c-jun在AR反式激活中的协同作用以及AR调节的SGCETV1、α和MRP4基因在前列腺癌中的作用的研究结果。在我的博士后培训中，我加入了贝丝以色列女执事医学中心(BIDMC)/哈佛医学院的Steven Balk实验室，专注于了解AR在致命形式的前列腺癌(CRPC)中的作用，这种形式会对雄激素剥夺疗法(ADT)产生抵抗。巴尔克实验室的研究重点是PCA和AR，该实验室的资金来自多个来源，包括NIH R01支持、前列腺癌孢子、国防部前列腺癌计划和PCF挑战赠款。我最初的研究是研究AR和HER信号的串扰，然后进入研究TMPRSS2：ERG融合基因在前列腺癌中的领域。利用融合阳性细胞系，我已经建立了明显模拟CRPC进展的异种移植模型。对该模型的研究得到了三个主要发现：(1)SOX9被鉴定为TMPRSS2的主要下游效应因子：融合阳性PCa中的ERG；(2)肿瘤内雄激素合成增加介导了肿瘤对ADT的耐药性和CYP17A1抑制；(3)CRPC中AR表达的增加是由于解除了其自身基因的AR抑制。AR在初级PCa中起着关键作用，并在CRPC中恢复其功能。与AR对基因转录的激活作用形成鲜明对比的是，人们对其抑制作用知之甚少。这一建议主要集中在阐明AR介导的基因转录抑制的分子机制。我在2年指导阶段的近期目标是探索AR通过结合其内含子2位点(ARBS2)并抑制基因转录而介导其自身基因表达的分子基础和临床意义。其他几个调节雄激素合成基因(HSD17B6和AKR1C3)表达的AR抑制基因位点也将被研究。特别是，染色质上的阻遏复合体及其导致ARBS2的表观遗传修饰并调节其活性的作用将被识别。更重要的是，任何将AR区分为激活剂和抑制物的不同机制都需要阐明。这些发现也将被转化为临床治疗，以增强ARBS2的活性，而不影响AR激活的基因位点。对于包括3年独立期在内的长期目标，AR基因位点的研究结果将扩展到PCa细胞的整个基因组。利用下一代测序和高通量数据生物信息学分析的优势，将在PCa细胞中鉴定由AR介导的全局抑制元件，并研究它们的功能。此外，AR相互作用的抑制子复合体在基因转录和前列腺癌发生和发展中的全球作用也将在提案阶段进行研究。目前的发现清楚地表明，我们还没有完全了解AR是如何发挥作用的，进一步的新的作用机制可能有助于它对基因亚集的调节。由于AR调节许多细胞通路中涉及的大量基因，因此选择性地靶向这些基因亚群的潜在能力对前列腺癌和其他疾病的治疗具有广泛的意义。