Protein Arginine Methyltransferase 5 Promotes pICln-Dependent Androgen Receptor Transcription in Castration-Resistant Prostate Cancer.

Abstract

The majority of advanced prostate cancer therapies aim to inhibit androgen receptor (AR) signaling. However, AR reactivation inevitably drives disease progression to castration-resistant prostate cancer (CRPC). Here we demonstrate that protein arginine methyltransferase 5 (PRMT5) functions as an epigenetic activator of AR transcription in CRPC, requiring cooperation with a methylosome subunit pICln. In vitro and in xenograft tumors in mice, targeting PRMT5 or pICln suppressed growth of CRPC cells. Full-length AR and AR-V7 transcription activation required both PRMT5 and pICln but not MEP50. This activation of transcription was accompanied by PRMT5-mediated symmetric dimethylation of H4R3 at the proximal AR promoter. Further, knockdown of PRMT5 abolished the binding of pICln (but not vice versa) to the AR proximal promoter region, suggesting that PRMT5 recruits pICln to the AR promoter to activate AR transcription. Differential gene expression analysis in 22Rv1 cells confirmed that PRMT5 and pICln both regulate the androgen signaling pathway. In addition, PRMT5 and pICln protein expression positively correlated with AR and AR-V7 protein expression in CRPC tissues and their expression was highly correlated at the mRNA level across multiple publicly available CRPC datasets. Our results suggest that targeting PRMT5 or pICln may be explored as a novel therapy for CRPC treatment by suppressing expression of AR and AR splice variants to circumvent AR reactivation. SIGNIFICANCE: This study provides evidence that targeting PRMT5 can eliminate expression of AR and can be explored as a novel therapeutic approach to treat metastatic hormone-naïve and castration-resistant prostate cancer.

• Authors: Elena Beketova, Shuyi Fang, Jake L Owens, Sheng Liu, Xufeng Chen, Qingfu Zhang, Andrew M Asberry, Xuehong Deng, Jonathan Malola, Jiaoti Huang, Chenglong Li, Roberto Pili, Bennett D Elzey, Timothy L Ratliff, Jun Wan, Chang-Deng Hu
• Journal: Cancer research (Cancer Res) Vol. 80 Issue 22 Pg. 4904-4917 (11 15 2020) ISSN: 1538-7445 [Electronic] United States
• PMID: 32999000 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: ©2020 American Association for Cancer Research.

Chemical References

• AR protein, human
• Adaptor Proteins, Signal Transducing
• CLNS1A protein, human
• Ion Channels
• MEP50 protein, human
• Receptors, Androgen
• Receptors, Histamine H2
• Receptors, Histamine H3
• PRMT5 protein, human
• Protein-Arginine N-Methyltransferases

Topics

• Adaptor Proteins, Signal Transducing (metabolism)
• Animals
• Cell Enlargement
• Disease Progression
• Down-Regulation
• Epigenesis, Genetic (physiology)
• Gene Expression Profiling
• Gene Knockdown Techniques
• Heterografts
• Humans
• Ion Channels (antagonists & inhibitors, genetics, metabolism)
• Male
• Methylation
• Mice
• Neoplasm Transplantation
• Promoter Regions, Genetic
• Prostatic Neoplasms, Castration-Resistant (metabolism)
• Protein-Arginine N-Methyltransferases (antagonists & inhibitors, genetics, physiology)
• Receptors, Androgen (metabolism)
• Receptors, Histamine H2 (metabolism)
• Receptors, Histamine H3 (metabolism)