p300-Mediated Acetylation of Histone Demethylase JMJD1A Prevents Its Degradation by Ubiquitin Ligase STUB1 and Enhances Its Activity in Prostate Cancer.

Abstract

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.

• Authors: Songhui Xu, Lingling Fan, Hee-Young Jeon, Fengbo Zhang, Xiaolu Cui, McKayla B Mickle, Guihong Peng, Arif Hussain, Ladan Fazli, Martin E Gleave, Xuesen Dong, Jianfei Qi
• Journal: Cancer research (Cancer Res) Vol. 80 Issue 15 Pg. 3074-3087 (08 01 2020) ISSN: 1538-7445 [Electronic] United States
• PMID: 32522824 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: ©2020 American Association for Cancer Research.

Chemical References

• AR protein, human
• BRD4 protein, human
• Cell Cycle Proteins
• Receptors, Androgen
• Transcription Factors
• Jumonji Domain-Containing Histone Demethylases
• KDM3A protein, human
• p300-CBP Transcription Factors
• p300-CBP-associated factor
• STUB1 protein, human
• Ubiquitin-Protein Ligases

Topics

• Acetylation
• Animals
• Cell Cycle Proteins (metabolism)
• Cells, Cultured
• Enzyme Activation (genetics)
• HEK293 Cells
• Humans
• Jumonji Domain-Containing Histone Demethylases (genetics, metabolism)
• Male
• Mice
• Mice, Nude
• PC-3 Cells
• Prostatic Neoplasms, Castration-Resistant (genetics, metabolism, pathology)
• Protein Processing, Post-Translational
• Proteolysis
• Receptors, Androgen (metabolism)
• Transcription Factors (metabolism)
• Ubiquitin-Protein Ligases (metabolism)
• p300-CBP Transcription Factors (metabolism)