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

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， 前列腺癌的遗传毒性疗法。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。

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.