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

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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.