MP90-04 A ROLE FOR HISTONE DEMETHYALASE JMJD1A IN THE DNA DAMAGE RESPONSE OF PROSTATE CANCER CELLS (2016)

You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology IV1 Apr 2016MP90-04 A ROLE FOR HISTONE DEMETHYALASE JMJD1A IN THE DNA DAMAGE RESPONSE OF PROSTATE CANCER CELLS Lingling Fan, Guihong Peng, Natasha Sahgal, Ladan Fazli, Martin Gleave, Yuji Zhang, Arif Hussain, Feyruz Rassool, and jianfei qi Lingling FanLingling Fan More articles by this author , Guihong PengGuihong Peng More articles by this author , Natasha SahgalNatasha Sahgal More articles by this author , Ladan FazliLadan Fazli More articles by this author , Martin GleaveMartin Gleave More articles by this author , Yuji ZhangYuji Zhang More articles by this author , Arif HussainArif Hussain More articles by this author , Feyruz RassoolFeyruz Rassool More articles by this author , and jianfei qijianfei qi More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.2548AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The major therapies for prostate cancer (PCa) such as radio-, chemo- or androgen deprivation therapy induce DNA damage. Thus the DNA damage response (DDR) and expression of DDR genes are key factors in determining outcome of PCa therapies. Histone demethylase JMJD1A regulates the gene expression by demethylating H3K9. Our previous work shows that JMJD1A is essential for the long-term proliferation and survival of PCa cells in vitro or in the xenograft prostate tumor model, partly via its effect on the activities of androgen receptor (AR) and c-Myc transcription factors. Here, we find a new role for JMJD1A in the expression of DDR genes and sensitivity of PCa cells to irradiation and androgen deprivation. METHODS Real-time PCR was used to measure the mRNA levels of some DDR genes in the PCa cells (control or siRNA knockdown (KD) of JMJD1A, AR or c-Myc). Chromatin immunoprecipitation (ChIP) was used to evaluate the binding of JMJD1A to the AR or MYC binding sites on these DDR genes. JMJD1A-KD PCa cells were treated with or without ionizing radiation (IR), and analyzed by the r-H2AX staining (a widely used marker for the DNA double strand breaks (DSBs)), western blot analysis of DNA damage signaling proteins, flow cytometry analysis of cell cycle, and GFP reporter assays for the DSB repair via the homologous recombination (HR) or non-homologous end joining (NHEJ) pathways. The growth of these PCa cells was also measured under the IR and androgen deprivation conditions. RESULTS JMJD1A was found to promote the expression of some DDR genes by co-activating AR and/or c-Myc. The DDR genes regulated by JMJD1A encode factors mediating the DSB repair by both HR and NHEJ pathways. JMJD1A KD led to increased r-H2AX foci in the non-irradiated cells, and the delayed clearance of r-H2AX foci in the irradiated cells. JMJD1A KD also increased the levels of phospho-DNA-PK or phospho-CHEK2 in the western blot analysis and caused G2 cell cycle arrest. Consistently, JMJD1A KD reduced the percentage of GFP-positive cells that reflects the DSB repair by both HR and NHEJ pathways. JMJD1A-KD cells showed a reduced growth under IR and androgen deprivation conditions. CONCLUSIONS JMJD1A promotes the DSB repair via regulation of DDR gene expression through AR and/or c-Myc. The role of JMJD1A in the DSB repair may contribute to the resistance of PCa cells to the radio- and androgen deprivation therapies. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e1146 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Lingling Fan More articles by this author Guihong Peng More articles by this author Natasha Sahgal More articles by this author Ladan Fazli More articles by this author Martin Gleave More articles by this author Yuji Zhang More articles by this author Arif Hussain More articles by this author Feyruz Rassool More articles by this author jianfei qi More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...