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

基本信息

批准号：
9068848
负责人：
Changmeng Cai
金额：
$ 24.22万
依托单位：
UNIVERSITY OF MASSACHUSETTS BOSTON
依托单位国家：
美国
项目类别：
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/9068848
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 Chips Gene Expression Gene Expression Regulation Genes Genetic Transcription 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 whole genome

项目摘要

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，我与托莱多大学（University of Toledo）的Lirim Shemshedini博士一起研究基因前列腺癌（PCA）中对雄激素受体（AR）的调节。我已经发布了研究C-Jun在AR反式激活以及AR调节的SGCα1，ETV1和MRP4基因在PCA中的作用的合作作用的结果。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）/哈佛医学院的史蒂文·巴克实验室（Steven Balk Lab），并专注于了解AR在PCA（CRPC）中的作用，从而发展了对雄激素剥夺治疗（ADT）的抵抗力。 Balk Lab中的研究集中在PCA和AR上，该实验室获得了来自NIH R01支持，前列腺癌孢子，DOD前列腺癌计划和PCF Challenge Grant在内的多个来源的资金。我最初的研究是研究AR和她的信号传导的串扰，然后我搬到了PCA中研究TMPRSS2：ERG融合基因的领域。使用融合阳性细胞系，我建立了明显模仿CRPC进展的异种移植模型。研究该模型导致了三个主要发现：（1）Sox9被确定为融合阳性PCA中TMPRSS2：ERG的主要下游效应子；（2）增加的肿瘤内雄激素合成介导了对ADT和CYP17A1抑制的肿瘤抗性；（3）CRPC中AR表达的增加是由于缓解了AR抑制其自身基因的抑制作用。 AR在原发性PCA中起关键作用，并在CRPC中继续其功能。与基因转录上的AR激活功能相反，其抑制功能知之甚少。该建议主要集中于阐明AR介导的基因转录表示的分子机制。我的2年修补阶段的直接目标是通过AR的分子基础和临床相关性，通过其内含子2位点（ARBS2）（ARBS2）的结合并抑制基因转录来介导其自身的基因表达。其他几种AR抑制的基因局部介导雄激素合成基因（HSD17B6和AKR1C3）的表达也将进行研究。特别是，将鉴定出对染色质及其作用的复制络合物，从而导致对ARBS2的表观遗传修饰并调节其活性。更重要的是，必须阐明任何将AR作为激活剂与复制品分开的不同机制。这些发现也将转化为临床疗法，以增强ARBS2的活性，但不会影响AR激活的基因基因座。对于包括3年独立阶段的长期目标，AR基因基因座的发现将扩展到PCA细胞的整个基因组。在高吞吐量数据上，将下一代测序和生物信息学分析的优势鉴定，将在PCA细胞中识别全局AR介导的抑制元件，并且其功能也将研究。此外，AR相互作用复合物在基因转录和前列腺癌的启动和进展方面的全球作用也将在建议阶段进行研究。当前的发现清楚地表明，我们尚未完全理解AR的功能，进一步的新型作用机理可能有助于其对基因子集的调节。随着AR调节许多细胞途径涉及的大量基因，选择性靶向这些基因子集的潜在能力对PCA和其他疾病的治疗具有广泛的影响。