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
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