Histone demethylase JMJD1A promotes expression of DNA repair factors and radio-resistance of prostate cancer cells
Open Access
- 1 April 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cell Death & Disease
- Vol. 11 (4), 1-16
- https://doi.org/10.1038/s41419-020-2405-4
Abstract
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 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.Keywords
Funding Information
- U.S. Department of Health & Human Services | NIH | National Cancer Institute (R01CA207118)
- V Foundation for Cancer Research (V2016-026)
This publication has 49 references indexed in Scilit:
- BRCA1–BARD1 promotes RAD51-mediated homologous DNA pairingNature, 2017
- Structural and functional characterization of the PNKP–XRCC4–LigIV DNA repair complexNucleic Acids Research, 2017
- JMJD1A is a signal-sensing scaffold that regulates acute chromatin dynamics via SWI/SNF association for thermogenesisNature Communications, 2015
- The histone demethylase KDM3A is a microRNA-22-regulated tumor promoter in Ewing SarcomaOncogene, 2013
- Androgen Receptor Signaling Regulates DNA Repair in Prostate CancersCancer Discovery, 2013
- Skp2 E3 Ligase Integrates ATM Activation and Homologous Recombination Repair by Ubiquitinating NBS1Molecular Cell, 2012
- Alternative-NHEJ Is a Mechanistically Distinct Pathway of Mammalian Chromosome Break RepairPLoS Genetics, 2008
- ATM Activation by DNA Double-Strand Breaks Through the Mre11-Rad50-Nbs1 ComplexScience, 2005
- Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymeraseNature, 2005
- The CDK regulates repair of double-strand breaks by homologous recombination during the cell cycleThe EMBO Journal, 2004