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.
Keywords:
PRMT5; TMPRSS2:ERG; androgen receptor; cancer biology; cell biology; human; prostate cancer.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Base Sequence
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Cell Differentiation
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Cell Line, Tumor
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Cell Proliferation
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Epithelial Cells / metabolism*
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Epithelial Cells / pathology
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Gene Expression Regulation, Neoplastic*
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Humans
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Male
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Methylation
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Models, Molecular
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Mutation
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Oncogene Proteins, Fusion / genetics*
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Oncogene Proteins, Fusion / metabolism
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Prostate / metabolism
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Prostate / pathology
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Protein Binding
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Protein Interaction Domains and Motifs
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Protein Multimerization
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Protein Structure, Secondary
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Protein-Arginine N-Methyltransferases / antagonists & inhibitors
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Protein-Arginine N-Methyltransferases / genetics*
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Protein-Arginine N-Methyltransferases / metabolism
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Receptors, Androgen / chemistry
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Receptors, Androgen / genetics*
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Receptors, Androgen / metabolism
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Serine Endopeptidases / genetics*
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Serine Endopeptidases / metabolism
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Signal Transduction
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Transcriptional Regulator ERG / genetics
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Transcriptional Regulator ERG / metabolism
Substances
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AR protein, human
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ERG protein, human
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Oncogene Proteins, Fusion
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RNA, Small Interfering
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Receptors, Androgen
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Transcriptional Regulator ERG
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PRMT5 protein, human
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Protein-Arginine N-Methyltransferases
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Serine Endopeptidases
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TMPRSS2 protein, human
Grants and funding
All authors except Thomas Westerling, Gilles Buchwalter, and Myles Brown received no external funding for this work.