p300-Mediated Acetylation of Histone Demethylase JMJD1A Prevents Its Degradation by Ubiquitin Ligase STUB1 and Enhances Its Activity in Prostate Cancer
单位：[1]Department of Biochemistry and Molecular Biology, University of Maryland, Baltimore, MD, USA.[2]Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD, USA.[3]Department ofUrology, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China.首都医科大学附属北京友谊医院[4]Department ofUrology, First Hospital of China Medical University, Shenyang, 110001, China.[5]Baltimore VA MedicalCenter, Baltimore, MD, USA.[6]Vancouver Prostate Centre, University of British Columbia, Vancouver, BC,Canada.
The androgen receptor (AR) pathway plays a central role in the development of castration-resistant prostate cancer (CRPC). The histone demethylase JMJD1A has been shown to regulate activities of AR and c-Myc transcription factors and promote prostate cancer progression. Here, we report that JMJD1A protein stability is controlled by the ubiquitin ligase STUB1. High levels of JMJD1A were strongly correlated with low STUB1 levels in human CRPC specimens. STUB1 inhibited AR activity, AR-V7 levels, and prostate cancer cell growth partly through degradation of JMJD1A. Furthermore, the acetyltransferase p300 acetylated JMJD1A at lysine (K) 421, a modification that recruits the BET family member BRD4 to block JMJD1A degradation and promote JMJD1A recruitment to AR targets. Increased levels of both total and K421-acetylated JMJD1A were observed in prostate cancer cells as they developed resistance to the AR antagonist enzalutamide. Treatment of prostate cancer cells with either p300 or BET inhibitors destabilized JMJD1A, and enzalutamide-resistant prostate cancer cells were more sensitive than parental cells to these inhibitors. Together, our findings identify a critical role for acetylation of JMJD1A in regulating JMJD1A stability and AR activity in CRPC. These newly identified mechanisms controlling JMJD1A protein stability provide potential druggable targets to encourage the development of additional therapies for advanced prostate cancer. Significance: Identification of mechanisms regulating JMJD1A protein stability reveals new strategies to destabilize JMJD1A and concomitantly inhibit AR activities as potential prostate cancer 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 Comprehensive Cancer Center, Baltimore, MD, USA.
共同第一作者：
通讯机构：[*1]Marlene and Stewart Greenebaum Comprehensive Cancer Center, Department of Biochemistry and Molecular Biology, University of Maryland, 655 W Baltimore St, Baltimore, MD, 21201 USA.
推荐引用方式(GB/T 7714)：
Songhui Xu,Lingling Fan,Hee-Young Jeon,et al.p300-Mediated Acetylation of Histone Demethylase JMJD1A Prevents Its Degradation by Ubiquitin Ligase STUB1 and Enhances Its Activity in Prostate Cancer[J].CANCER RESEARCH.2020,80(15):3074-3087.doi:10.1158/0008-5472.CAN-20-0233.
APA：
Songhui Xu,Lingling Fan,Hee-Young Jeon,Fengbo Zhang,XiaoluCui...&Jianfei Qi.(2020).p300-Mediated Acetylation of Histone Demethylase JMJD1A Prevents Its Degradation by Ubiquitin Ligase STUB1 and Enhances Its Activity in Prostate Cancer.CANCER RESEARCH,80,(15)
MLA：
Songhui Xu,et al."p300-Mediated Acetylation of Histone Demethylase JMJD1A Prevents Its Degradation by Ubiquitin Ligase STUB1 and Enhances Its Activity in Prostate Cancer".CANCER RESEARCH 80..15(2020):3074-3087
医学