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.

抽象的 PCA是美国男性最常见的恶性肿瘤。晚期PCA的疗法包括雄激素剥夺治疗（ADT），化学疗法和放疗，所有这些都会诱导DNA损伤。因此 DNA损伤反应和DNA修复基因的表达是确定结果的关键因素 PCA的遗传毒性疗法。我们已经确定了组蛋白脱甲基酶JMJD1A的途径通过E3泛素连接酶Huwe1进行非典型的泛素化，从而增强了JMJD1A 雄激素受体和C-MYC转录因子的共激活。在这里，我们将检验以下假设 JMJD1A的非典型泛素化调节DNA修复基因通过AR和C-MYC的表达，而在电离辐射（IR）和雄激素剥夺条件下促进PCA细胞的生长和存活。 AIM ONE将评估调节AR和C-MYC转录活性的JMJD1A机制。目标两个意志在体外研究IR和雄激素剥夺后的DNA损伤反应中的JMJD1A功能。瞄准三将评估JMJD1A的功能在异种移植的前列腺肿瘤对casttration和ir的反应中。最后，在目标四，我们将研究包含HUWE1/JMJD1A/DNA修复基因的因子的异常表达人PCA组织微阵列（TMA）中的途径。我们提出的研究应定义一种新途径，包括JMJDJ1A及其目标和调节剂，该靶标和监管机构对PCA对ADT和放射疗法的反应。如果成功，这项工作可能会确定用于抗PCA疗法的新治疗靶标或标记。