title: ERG signaling in prostate cancer is driven through PRMT5-dependent methylation of the Androgen Receptor.
abstract: The TMPRSS2:ERG gene fusion is common in androgen receptor (AR) positive prostate cancers, yet its function remains poorly understood. From a screen for functionally relevant ERG interactors, we identify the arginine methyltransferase PRMT5. ERG recruits PRMT5 to AR-target genes, where PRMT5 methylates AR on arginine 761. This attenuates AR recruitment and transcription of genes expressed in differentiated prostate epithelium. The AR-inhibitory function of PRMT5 is restricted to TMPRSS2:ERG-positive prostate cancer cells. Mutation of this methylation site on AR results in a transcriptionally hyperactive AR, suggesting that the proliferative effects of ERG and PRMT5 are mediated through attenuating AR's ability to induce genes normally involved in lineage differentiation. This provides a rationale for targeting PRMT5 in TMPRSS2:ERG positive prostate cancers. Moreover, methylation of AR at arginine 761 highlights a mechanism for how the ERG oncogene may coax AR towards inducing proliferation versus differentiation.
authors.affiliation: Department of Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States.
authors.forename: Zineb
authors.initials: Z
authors.lastname: Mounir
authors.affiliation: Department of Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Korn
authors.affiliation: Department of Medical Oncology, Harvard Medical School, Boston, United States.|Center for Functional Cancer Epigenetics, Harvard Medical School, Boston, United States.|Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States.
authors.forename: Thomas
authors.initials: T
authors.lastname: Westerling
authors.affiliation: Department of Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States.
authors.forename: Fallon
authors.initials: F
authors.lastname: Lin
authors.affiliation: Center for Proteomic Chemistry, Novartis Institutes for BioMedical Research, Cambridge, United States.
authors.forename: Christina A
authors.initials: CA
authors.lastname: Kirby
authors.affiliation: Developmental and Molecular Pathways, Novartis Institutes for Biomedical Research, Cambridge, United States.
authors.forename: Markus
authors.initials: M
authors.lastname: Schirle
authors.affiliation: Developmental and Molecular Pathways, Novartis Institutes for Biomedical Research, Cambridge, United States.
authors.forename: Gregg
authors.initials: G
authors.lastname: McAllister
authors.affiliation: Developmental and Molecular Pathways, Novartis Institutes for Biomedical Research, Cambridge, United States.
authors.forename: Greg
authors.initials: G
authors.lastname: Hoffman
authors.affiliation: Developmental and Molecular Pathways, Novartis Institutes for Biomedical Research, Cambridge, United States.
authors.forename: Nadire
authors.initials: N
authors.lastname: Ramadan
authors.affiliation: Genomics Institute of the Novartis Research Foundation, Novartis Institutes for Bio Medical Resarch, San Diego, United States.
authors.forename: Anke
authors.initials: A
authors.lastname: Hartung
authors.affiliation: Developmental and Molecular Pathways, Novartis Institutes for Biomedical Research, Cambridge, United States.
authors.forename: Yan
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Department of Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States.
authors.forename: David Randal
authors.initials: DR
authors.lastname: Kipp
authors.affiliation: Department of Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States.
authors.forename: Christopher
authors.initials: C
authors.lastname: Quinn
authors.affiliation: Department of Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States.
authors.forename: Michelle
authors.initials: M
authors.lastname: Fodor
authors.affiliation: Department of Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States.
authors.forename: Jason
authors.initials: J
authors.lastname: Baird
authors.affiliation: Department of Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States.
authors.forename: Marie
authors.initials: M
authors.lastname: Schoumacher
authors.affiliation: Department of Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States.
authors.forename: Ronald
authors.initials: R
authors.lastname: Meyer
authors.affiliation: Department of Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States.
authors.forename: James
authors.initials: J
authors.lastname: Deeds
authors.affiliation: Department of Medical Oncology, Harvard Medical School, Boston, United States.|Center for Functional Cancer Epigenetics, Harvard Medical School, Boston, United States.|Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States.
authors.forename: Gilles
authors.initials: G
authors.lastname: Buchwalter
authors.affiliation: Center for Proteomic Chemistry, Novartis Institutes for BioMedical Research, Cambridge, United States.
authors.forename: Travis
authors.initials: T
authors.lastname: Stams
authors.affiliation: Department of Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Keen
authors.affiliation: Department of Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States.
authors.forename: William R
authors.initials: WR
authors.lastname: Sellers
authors.affiliation: Department of Medical Oncology, Harvard Medical School, Boston, United States.|Center for Functional Cancer Epigenetics, Harvard Medical School, Boston, United States.|Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States.
authors.forename: Myles
authors.identifier: 0000-0002-8213-1658
authors.initials: M
authors.lastname: Brown
authors.affiliation: Department of Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States.
authors.forename: Raymond A
authors.identifier: 0000-0001-8920-8198
authors.initials: RA
authors.lastname: Pagliarini
mesh_terms: D001483:Base Sequence; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008745:Methylation; D008958:Models, Molecular; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D011467:Prostate / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D011484:Protein-Arginine N-Methyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D000071230:Transcriptional Regulator ERG / Q000235:genetics / Q000378:metabolism
chemical_list: C410798:AR protein, human; C072312:ERG protein, human; D015514:Oncogene Proteins, Fusion; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; D000071230:Transcriptional Regulator ERG; C400529:PRMT5 protein, human; D011484:Protein-Arginine N-Methyltransferases; D012697:Serine Endopeptidases; C421305:TMPRSS2 protein, human
keywords: PRMT5; TMPRSS2:ERG; androgen receptor; cancer biology; cell biology; human; prostate cancer