ERG signaling in prostate cancer is driven through PRMT5-dependent methylation of the Androgen Receptor
Autor: | Thomas Westerling, Marie Schoumacher, Christopher Quinn, James Deeds, Markus Schirle, Joshua M. Korn, Raymond Pagliarini, Yan Feng, Ronald Meyer, Nicholas Keen, Zineb Mounir, Gregg McAllister, Greg Hoffman, Michelle Fodor, Fallon Lin, Anke Hartung, Christina A. Kirby, David Randal Kipp, Gilles Buchwalter, William R. Sellers, Myles Brown, Travis Stams, Jason Baird, Nadire Ramadan |
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Jazyk: | angličtina |
Rok vydání: | 2016 |
Předmět: |
Male
Models Molecular 0301 basic medicine Protein-Arginine N-Methyltransferases Oncogene Proteins Fusion genetic structures Protein Structure Secondary Fusion gene Prostate cancer 0302 clinical medicine androgen receptor RNA Small Interfering Biology (General) Cancer Biology Transcriptional Regulator ERG General Neuroscience Protein arginine methyltransferase 5 Serine Endopeptidases Prostate Cell Differentiation General Medicine Chromoplexy Methylation prostate cancer Gene Expression Regulation Neoplastic Receptors Androgen 030220 oncology & carcinogenesis PRMT5 Medicine Protein Binding Signal Transduction Human medicine.medical_specialty QH301-705.5 Science Short Report Biology TMPRSS2 General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Cell Line Tumor Internal medicine medicine Humans Protein Interaction Domains and Motifs Cell Proliferation Base Sequence General Immunology and Microbiology Epithelial Cells Cell Biology medicine.disease eye diseases Androgen receptor TMPRSS2:ERG 030104 developmental biology Endocrinology Mutation Cancer research sense organs Protein Multimerization |
Zdroj: | eLife, Vol 5 (2016) eLife |
Popis: | 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. DOI: http://dx.doi.org/10.7554/eLife.13964.001 eLife digest Prostate cancers are among the most common types of cancer in men, which, like other cancers, are driven by genetic mutations. Roughly half of all prostate cancers contain a genetic change that incorrectly fuses two genes together, causing the cells to produce abnormally high levels of a protein called ERG. ERG is a transcription factor, a protein that binds to specific sequences of DNA to influence the activity of nearby genes. ERG represses genes that help to prevent prostate cancers from growing, and so promotes prostate cancer development. Like most other transcription factors, ERG is difficult to target with drugs and no therapies that directly prevent the activity of ERG currently exist. Mounir et al. wanted to find out whether ERG cooperates with other proteins to cause prostate cancer cells to grow, with the hope that these proteins could be more easily targeted with a drug. By using various biochemical techniques in human prostate cancer cell lines, Mounir et al. found that ERG interacts with an enzyme called PRMT5. This interaction enables PRMT5 to chemically modify other proteins to change their activity. In the case of prostate cancer cells, PRMT5 inappropriately modifies the androgen receptor, a protein that regulates the growth of normal prostate cells. This abnormal modification contributes to the excessive growth of the cancer cells. Although PRMT5 will be easier to target with drugs than ERG, it also has many other roles besides those described by Mounir et al. Much more work is therefore needed to investigate whether PRMT5 could be safely targeted to treat patients with prostate cancer. DOI: http://dx.doi.org/10.7554/eLife.13964.002 |
Databáze: | OpenAIRE |
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