title: Protein arginine methyltransferase 5 functions as an epigenetic activator of the androgen receptor to promote prostate cancer cell growth.
abstract: Protein arginine methyltransferase 5 (PRMT5) is an emerging epigenetic enzyme that mainly represses transcription of target genes via symmetric dimethylation of arginine residues on histones H4R3, H3R8 and H2AR3. Accumulating evidence suggests that PRMT5 may function as an oncogene to drive cancer cell growth by epigenetic inactivation of several tumor suppressors. Here, we provide evidence that PRMT5 promotes prostate cancer cell growth by epigenetically activating transcription of the androgen receptor (AR) in prostate cancer cells. Knockdown of PRMT5 or inhibition of PRMT5 by a specific inhibitor reduces the expression of AR and suppresses the growth of multiple AR-positive, but not AR-negative, prostate cancer cells. Significantly, knockdown of PRMT5 in AR-positive LNCaP cells completely suppresses the growth of xenograft tumors in mice. Molecular analysis reveals that PRMT5 binds to the proximal promoter region of the AR gene and contributes mainly to the enriched symmetric dimethylation of H4R3 in the same region. Mechanistically, PRMT5 is recruited to the AR promoter by its interaction with Sp1, the major transcription factor responsible for AR transcription, and forms a complex with Brg1, an ATP-dependent chromatin remodeler, on the proximal promoter region of the AR gene. Furthermore, PRMT5 expression in prostate cancer tissues is significantly higher than that in benign prostatic hyperplasia tissues, and PRMT5 expression correlates positively with AR expression at both the protein and mRNA levels. Taken together, our results identify PRMT5 as a novel epigenetic activator of AR in prostate cancer. Given that inhibiting AR transcriptional activity or androgen synthesis remains the major mechanism of action for most existing anti-androgen agents, our findings also raise an interesting possibility that targeting PRMT5 may represent a novel approach for prostate cancer treatment by eliminating AR expression.
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USA.
authors.forename: X
authors.initials: X
authors.lastname: Deng
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USA.|Department of Basic Medical Sciences, School of Medicine, Jiangsu University, Zhenjiang, China.
authors.forename: G
authors.initials: G
authors.lastname: Shao
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USA.|Department of Orthopedics, Institute of Orthopedic Diseases, The First Affiliated Hospital, Jinan University, Guangzhou, China.
authors.forename: H-T
authors.initials: HT
authors.lastname: Zhang
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, Ohio State University, Columbus, OH, USA.
authors.forename: C
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Statistics, Purdue University, West Lafayette, IN, USA.
authors.forename: D
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, IN, USA.
authors.forename: L
authors.initials: L
authors.lastname: Cheng
authors.affiliation: Department of Comparative Pathobiology, Purdue University, West Lafayette, IN, USA.
authors.forename: B D
authors.initials: BD
authors.lastname: Elzey
authors.affiliation: Department of Medical Oncology, Indiana University Simon Cancer Center, Indianapolis, IN, USA.
authors.forename: R
authors.initials: R
authors.lastname: Pili
authors.affiliation: Department of Comparative Pathobiology, Purdue University, West Lafayette, IN, USA.|Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN, USA.
authors.forename: T L
authors.initials: TL
authors.lastname: Ratliff
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California at Los Angeles, Los Angeles, CA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USA.|Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN, USA.
authors.forename: C-D
authors.initials: CD
authors.lastname: Hu
mesh_terms: D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D057890:Epigenomics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011470:Prostatic Hyperplasia / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics / Q000378:metabolism*; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C410798:AR protein, human; D014408:Biomarkers, Tumor; D009687:Nuclear Proteins; D011944:Receptors, Androgen; D016329:Sp1 Transcription Factor; C108209:SP1 protein, human; D014157:Transcription Factors; C400529:PRMT5 protein, human; D011484:Protein-Arginine N-Methyltransferases; C084108:SMARCA4 protein, human; D004265:DNA Helicases