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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：
8533770
负责人：
Changmeng Cai
金额：
$ 13.49万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-17 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8533770
关键词：
Affect Androgen Receptor Androgens Basic Cancer Research Binding Binding Sites Bioinformatics CYP17A1 gene Cancer Biology Cancer Patient Cell Cycle Progression Cell Line ChIP-seq Chromatin Clinical Complex DNA biosynthesis Data Development Disease Doctor of Philosophy ETV1 gene Elements Epigenetic Process Faculty Feedback Funding Gene Amplification Gene Expression Gene Targeting Genes Genetic Transcription Genome Goals Hematology Histones Homeostasis Housing 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 Patient Care 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 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 oncology prevent programs prostate cancer cell receptor binding receptor expression receptor function transcription factor transcriptome sequencing tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): I started to study androgen receptor (AR) functions in prostate cancer in Lirim Shemshedini lab (University of Toledo) during my Ph.D.. In this period of study, I mainly focused on the roles of AR coactivators and AR target genes 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 SGC¿1, ETV1, and MRP4 genes in PCa. After I received my Ph.D., I joined Steven Balk lab at Beth Israel Deaconess Medical Center (BIDMC)/Harvard Medical School. This Cancer Biology Program is administratively housed within the Hematology-Oncology Division, which comprises a large faculty involved in patient care, clinical, translational, and basic cancer research. 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, and DoD Prostate Cancer program sources. In the lab, I continued to study the roles of AR in the lethal form of PCa that develops the resistance to androgen deprivation therapy (ADT). This form of cancer is called castration resistant prostate cancer, or CRPC. My initial study is focusing on AR regulation by 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 two major findings: (1) increased intratumoal androgen synthesis that mediates tumor resistance to ADT and CYP17A1 inhibition; (2) increased AR expression in CRPC is due to AR suppression of its own gene. AR plays a pivotal role in primary PCa and regains its functions in CRPC. In contrast to the well- established 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）：我在攻读博士学位期间开始在Lirim Shemshedini实验室（托莱多大学）研究前列腺癌中的雄激素受体（AR）功能。在这一阶段的研究中，我主要集中在AR辅激活因子和AR靶基因在前列腺癌（PCa）中的作用。我已经发表了研究c-Jun对AR反式激活的协同作用以及AR调节的PCa中的SGC <$1、ETV 1和MRP 4基因的作用的结果。我拿到博士学位后，我加入了Beth Israel Deaconess Medical Center（BIDMC）/哈佛医学院的Steven Balk实验室。该癌症生物学计划在行政上位于血液肿瘤学部门，该部门包括参与患者护理，临床，转化和基础癌症研究的大型教师。Balk实验室的研究重点是PCa和AR，该实验室拥有多个来源的资金，包括NIH R 01支持，前列腺癌SPORE和DoD前列腺癌计划来源。在实验室中，我继续研究AR在致死形式的PCa中的作用，PCa对雄激素剥夺疗法（ADT）产生抗性。这种形式的癌症被称为去势抵抗性前列腺癌，或CRPC。我最初的研究主要集中在HER信号对AR的调节，然后我转向了PCa中TMPRSS 2：ERG融合基因的研究。使用融合阳性细胞系，我已经建立了异种移植模型，清楚地模拟CRPC的进展。对该模型的研究导致了两个主要发现：（1）体内雄激素合成增加，介导了肿瘤对ADT和CYP 17 A1抑制的耐药性;（2）CRPC中AR表达增加是由于其自身基因的AR抑制。AR在原发性PCa中起关键作用，并在CRPC中恢复其功能。与已确立的AR对基因转录的激活功能相反，其抑制功能知之甚少。本研究主要致力于阐明AR介导的基因转录抑制的分子机制。我的2年指导阶段的直接目标将是追求AR通过其内含子2位点（ARBS 2）的结合和抑制基因转录介导其自身基因表达的分子基础和临床相关性。还将研究其他几个介导雄激素合成基因（HSD 17 B6和AKR 1C 3）表达的AR抑制基因位点。特别是，将鉴定染色质上的阻遏物复合物及其导致ARBS 2表观遗传修饰并调节其活性的作用。更重要的是，任何不同的机制，区分AR作为激活剂与阻遏物需要阐明。这些发现也将转化为临床治疗，以增强ARBS 2的活性，但不影响AR激活的基因位点。对于包括3年独立阶段的长期目标，AR基因位点的发现将扩展到PCa细胞的整个基因组。利用下一代测序技术和生物信息学分析技术，对前列腺癌细胞中AR介导的抑制因子进行鉴定，并对其功能进行研究。此外，AR相互作用的阻遏物复合物在基因转录和前列腺癌的发生和发展中的整体作用也将在提案阶段进行研究。目前的研究结果清楚地表明，我们还没有完全了解AR的功能，进一步的新的作用机制可能有助于其对基因子集的调节。由于AR调节参与许多细胞途径的大量基因，因此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意义。