单位：[1]Department of Biochemistry and Molecular Biology, University of Maryland,Baltimore, MD, USA[2]Marlene and Stewart Greenebaum ComprehensiveCancer Center, Baltimore, MD, USA[3]Department of Urology, Beijing FriendshipHospital, Capital Medical University, 100050 Beijing, China[4]Department ofUrology, First Hospital of China Medical University, 110001 Shenyang, China[5]Vancouver Prostate Centre, University of British Columbia, Vancouver, BC,Canada[6]Department of Anatomy and Neurobiology, University of Maryland,Baltimore, MD, USA[7]Department of Pathology, The Johns Hopkins University,Baltimore, MD, USA[8]Baltimore VA Medical Center, Baltimore, MD, USA[9]Department of Radiation Oncology, University of Maryland, Baltimore, MD,USA
The DNA damage response (DDR) pathway is a promising target for anticancer therapies. The androgen receptor and myeloblastosis transcription factors have been reported to regulate expression of an overlapping set of DDR genes in prostate cancer cells. Here, we found that histone demethylase JMJD1A regulates expression of a different set of DDR genes largely through c-Myc. Inhibition of JMJD1A delayed the resolution of gamma-H2AX foci, reduced the formation of foci containing ubiquitin, 53BP1, BRCA1 or Rad51, and inhibited the reporter activity of double-strand break (DSB) repair. Mechanistically, JMJD1A regulated expression of DDR genes by increasing not only the level but also the chromatin recruitment of c-Myc through H3K9 demethylation. Further, we found that ubiquitin ligase HUWE1 induced the K27-/K29-linked noncanonical ubiquitination of JMJD1A at lysine-918. Ablation of the JMJD1A noncanonical ubiquitination lowered DDR gene expression, impaired DSB repair, and sensitized response of prostate cells to irradiation, topoisomerase inhibitors or PARP inhibitors. Thus, development of agents that target JMJD1A or its noncanonical ubiquitination may sensitize the response of prostate cancer to radiotherapy and possibly also genotoxic therapy.
基金：
NCIUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [R01CA207118]; V Scholar award; Merit Review Award, Medical Research Service, Department of Veterans AffairsUS Department of Veterans Affairs [I01 BX000545]
第一作者单位：[1]Department of Biochemistry and Molecular Biology, University of Maryland,Baltimore, MD, USA[2]Marlene and Stewart Greenebaum ComprehensiveCancer Center, Baltimore, MD, USA
共同第一作者：
通讯作者：
通讯机构：[1]Department of Biochemistry and Molecular Biology, University of Maryland,Baltimore, MD, USA[2]Marlene and Stewart Greenebaum ComprehensiveCancer Center, Baltimore, MD, USA
推荐引用方式(GB/T 7714)：
Fan Lingling,Xu Songhui,Zhang Fengbo,et al.Histone demethylase JMJD1A promotes expression of DNA repair factors and radio-resistance of prostate cancer cells[J].CELL DEATH & DISEASE.2020,11(4):doi:10.1038/s41419-020-2405-4.
APA：
Fan, Lingling,Xu, Songhui,Zhang, Fengbo,Cui, Xiaolu,Fazli, Ladan...&Qi, Jianfei.(2020).Histone demethylase JMJD1A promotes expression of DNA repair factors and radio-resistance of prostate cancer cells.CELL DEATH & DISEASE,11,(4)
MLA：
Fan, Lingling,et al."Histone demethylase JMJD1A promotes expression of DNA repair factors and radio-resistance of prostate cancer cells".CELL DEATH & DISEASE 11..4(2020)
生物学