Histone demethylase JMJD1A promotes expression of DNA repair factors and radio-resistance of prostate cancer cells
JournalCell Death and Disease
MetadataShow full item record
AbstractThe 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 γ-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. Copyright 2020, The Author(s).
SponsorsThis study is supported by NCI grant R01CA207118 and a V Scholar award (to J.Q.). Part of A.H.'s time was supported by a Merit Review Award (I01 BX000545), Medical Research Service, Department of Veterans Affairs.
Identifier to cite or link to this itemhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85082790577&doi=10.1038%2fs41419-020-2405-4&partnerID=40&md5=bede8e0aaf6c59de4d012601769693eb; http://hdl.handle.net/10713/12542
- Regulation of c-Myc expression by the histone demethylase JMJD1A is essential for prostate cancer cell growth and survival.
- Authors: Fan L, Peng G, Sahgal N, Fazli L, Gleave M, Zhang Y, Hussain A, Qi J
- Issue date: 2016 May 12
- Histone demethylase JMJD1A promotes alternative splicing of AR variant 7 (AR-V7) in prostate cancer cells.
- Authors: Fan L, Zhang F, Xu S, Cui X, Hussain A, Fazli L, Gleave M, Dong X, Qi J
- Issue date: 2018 May 15
- p300-Mediated Acetylation of Histone Demethylase JMJD1A Prevents Its Degradation by Ubiquitin Ligase STUB1 and Enhances Its Activity in Prostate Cancer.
- Authors: Xu S, Fan L, Jeon HY, Zhang F, Cui X, Mickle MB, Peng G, Hussain A, Fazli L, Gleave ME, Dong X, Qi J
- Issue date: 2020 Aug 1
- A small ubiquitin binding domain inhibits ubiquitin-dependent protein recruitment to DNA repair foci.
- Authors: Helchowski CM, Skow LF, Roberts KH, Chute CL, Canman CE
- Issue date: 2013 Dec 15
- BRUCE regulates DNA double-strand break response by promoting USP8 deubiquitination of BRIT1.
- Authors: Ge C, Che L, Ren J, Pandita RK, Lu J, Li K, Pandita TK, Du C
- Issue date: 2015 Mar 17