Histone demethylase JMJD1A promotes expression of DNA repair factors and radio-resistance of prostate cancer cells

Lingling Fan,Ladan Fazli,Feyruz Rassool,Austin Yang,Martin Gleave,Xiaolu Cui,Fengbo Zhang,Jianfei Qi,Arif Hussain,Songhui Xu,David J Clark

doi: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.

Highlights

Metastatic castration-resistant prostate canceris incurable and underlies the mortality of most prostate cancer (PCa) patients
By re-examining the profiling array data (GSE70498), we found that JMJD1A knockdown reduced mRNA levels of several DNA damage response (DDR) genes (Fig. S1A)
NBS120, RNF821, RAD122, SMC1A23 and BARD124 are involved in double-strand break (DSB) repair via the homologous recombination (HR) pathway, while XRCC625, PRKDC25 and PNKP26 are involved in DSB repair via the nonhomologous end joining (NHEJ) pathway

Summary

Introduction

Is incurable and underlies the mortality of most prostate cancer (PCa) patients. Methylation of histone 3 lysine-9 (H3K9) is a repressive epigenetic modification. The histone demethylase JMJD1A removes mono- and di-methyl groups from H3K9 to enable transcriptional activation. JMJD1A is reportedly overexpressed and plays a tumor-promoting role in a JMJD1A regulates the activities of androgen receptor (AR) and c-Myc in PCa cells[12,13]. JMJD1A promotes the chromatin recruitment of AR through H3K9 demethylation[13], and enhances the generation of AR-V714, a hormoneindependent truncated form of AR. The proto-oncogene c-Myc forms a heterodimer with Max, and binds to the Enhancer Box (E box) sequence to regulate gene expression.

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Results

Conclusion