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Role of histone demethylase JMJD1A in the DNA damage response of prostate cancer cells

组蛋白去甲基化酶 JMJD1A 在前列腺癌细胞 DNA 损伤反应中的作用

基本信息

批准号：
9330125
负责人：
Jianfei Qi
金额：
$ 35.34万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-10 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9330125
关键词：
American Androgen Receptor Androgens Biochemical Castration Cells DNA Damage DNA Markers DNA Repair DNA Repair Gene DNA strand break DNA-dependent protein kinase Data Defect EP300 gene Gene Expression Gene Expression Regulation Genes Genetic Transcription Goals Growth Histones Human Immunohistochemistry Impairment In Vitro Injectable Ionizing radiation Lysine Malignant Neoplasms Malignant neoplasm of prostate Modification Monitor Mus Nude Mice Outcome Pathway interactions Phenotype Phosphorylation Process Prostate Prostate Cancer therapy Prostatic Neoplasms Proteins Proto-Oncogene Proteins c-myc Quantitative Reverse Transcriptase PCR Radiation Induced DNA Damage Radiation therapy Radio Radioresistance Recruitment Activity Reporting Role Staining method Stains Tail Testing Tissue Microarray Tissues Tumor Tissue Ubiquitination Western Blotting Work XRCC2 gene XRCC3 gene Xenograft procedure androgen deprivation therapy base c-myc Genes chemotherapy deprivation dosage gene function gene repair genotoxicity histone demethylase in vivo knock-down men mutant new therapeutic target novel outcome forecast overexpression prostate cancer cell prostate cancer cell line protein degradation protein function protein protein interaction radiation effect repaired research study response small hairpin RNA targeted treatment therapeutic biomarker tumor tumor growth tumor progression tumor xenograft tumorigenesis ubiquitin ligase ubiquitin-protein ligase

项目摘要

ABSTRACT PCa is the most common malignancy in American men. Therapies for advanced PCa include androgen deprivation therapy (ADT), chemotherapy and radiotherapy, all of which can induce the DNA damage. Thus the DNA damage response and expression of DNA repair genes are key factors in determining outcome of genotoxic therapies for PCa. We have identified a pathway in which the histone demethylase JMJD1A undergoes a non-canonical ubiquitination by the E3 ubiquitin ligase HUWE1, which in turn enhances JMJD1A co-activation of androgen receptor and c-Myc transcription factors. Here, we will test the hypothesis that the non-canonical ubiquitination of JMJD1A regulates expression of DNA repair genes through AR and c-Myc, and promotes growth and survival of PCa cells under ionizing radiation (IR) and androgen deprivation conditions. Aim one will assess JMJD1A mechanisms in regulating AR and c-Myc transcriptional activity. Aim two will investigate JMJD1A function in DNA damage responses after IR and androgen deprivation in vitro. Aim three will evaluate JMJD1A function in the response of xenografted prostate tumors to castration and IR. Finally, in Aim four, we will investigate the aberrant expression of factors comprising HUWE1/JMJD1A/DNA repair gene pathway in a human PCa tissue microarray (TMA). Our proposed studies should define a new pathway, including JMJDJ1A and its targets and regulators, that governs PCa responses to ADT and radiotherapy. If successful, this work may identify new therapeutic targets or markers for anti-PCa therapy.

摘要前列腺癌是美国男性最常见的恶性肿瘤。晚期前列腺癌的治疗包括雄激素剥夺疗法（ADT）、化疗和放疗均可引起DNA损伤。因此 DNA损伤反应和DNA修复基因的表达是决定预后的关键因素， PCa的遗传毒性治疗。我们已经确定了组蛋白去甲基化酶JMJD 1A 通过E3泛素连接酶HUWE 1进行非典型泛素化，这反过来增强了JMJD 1A 雄激素受体和c-Myc转录因子的共激活。在这里，我们将测试假设， JMJD 1A的非典型泛素化通过AR和c-Myc调节DNA修复基因的表达，促进PCa细胞在电离辐射（IR）和雄激素剥夺条件下的生长和存活。目的一是研究JMJD 1A在调节AR和c-Myc转录活性中的作用机制。瞄准二号意志研究JMJD 1A在体外IR和雄激素剥夺后DNA损伤反应中功能。瞄准三将评估JMJD 1A在异种移植前列腺肿瘤对去势和IR的反应中的功能。目的四，研究HUWE 1/JMJD 1A/DNA修复基因相关因子的异常表达在人PCa组织微阵列（TMA）中检测PCa通路。我们提出的研究应该能找到一条新的途径，包括JMJDJ 1A及其靶点和调节因子，其控制PCa对ADT和放疗的反应。如果成功，这项工作可能会确定新的治疗靶点或抗PCa治疗的标志物。