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.
We propose to characterize a pathway that regulates genes functioning in DNA repair and DNA damage responses in the context of prostate cancer (PCa). DNA damage responses are tightly associated with tumorigenesis, and proteins functioning in related pathways are important determinant for cancer outcome following radio-, chemo-, or androgen deprivation therapy. Thus, our studies should identify novel mechanisms modulating the sensitivity of human PCa to genotoxic therapies and could facilitate targeted therapy and tumor monitoring.
|Senft, Daniela; Qi, Jianfei; Ronai, Ze'ev A (2018) Ubiquitin ligases in oncogenic transformation and cancer therapy. Nat Rev Cancer 18:69-88|
|Fan, Lingling; Zhang, Fengbo; Xu, Songhui et al. (2018) Histone demethylase JMJD1A promotes alternative splicing of AR variant 7 (AR-V7) in prostate cancer cells. Proc Natl Acad Sci U S A 115:E4584-E4593|
|Wilson, Stephen; Fan, Lingling; Sahgal, Natasha et al. (2017) The histone demethylase KDM3A regulates the transcriptional program of the androgen receptor in prostate cancer cells. Oncotarget 8:30328-30343|