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方法包括雄激素 剥夺疗法(ADT)、化疗和放射治疗都会引起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 前列腺癌的基因毒性疗法。我们已经确定了组蛋白去甲基酶JMJD1A的一个途径 通过E3泛素连接酶HUWE1进行非典型的泛素化，进而增强JMJD1A 雄激素受体和c-Myc转录因子的共同激活。在这里，我们将检验这一假设 JMJD1A的非规范泛素化通过AR和c-Myc调节DNA修复基因的表达，并 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。 目的研究JMJD1A调节AR和c-Myc转录活性的机制。目标二意志 研究JMJD1A在体外IR和去雄激素后DNA损伤反应中的作用。目标三 将评估JMJD1A在异种移植前列腺肿瘤对去势和IR的反应中的作用。最后，在 目的研究HUWE1/JMJD1A/DNA修复基因相关因子的异常表达 人前列腺癌组织微阵列(TMA)中的途径。我们提议的研究应该定义一条新的途径， 包括JMJDJ1A及其靶点和调节器，管理对ADT和放射治疗的PCA反应。如果 如果成功，这项工作可能会为抗前列腺癌治疗确定新的治疗靶点或标记物。

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.