Phosphorylation of the oncogenic transcription factor ERG in prostate cells dissociates polycomb repressive complex 2, allowing target gene activation
| Autor: | Brady G. Strittmatter, Vivekananda Kedage, Peter C. Hollenhorst, Paige Dausinas |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male Transcriptional Activation genetic structures Biochemistry TMPRSS2 Cell Line 03 medical and health sciences Prostate cancer 0302 clinical medicine Transcriptional Regulator ERG Gene expression medicine SUZ12 Humans Gene Regulation Phosphorylation Extracellular Signal-Regulated MAP Kinases Molecular Biology Transcription factor Chemistry ETS transcription factor family EZH2 Polycomb Repressive Complex 2 Prostate Prostatic Neoplasms Cell Biology medicine.disease eye diseases Neoplasm Proteins Gene Expression Regulation Neoplastic 030104 developmental biology 030220 oncology & carcinogenesis Cancer research sense organs |
| Zdroj: | The Journal of biological chemistry. 292(42) |
| ISSN: | 1083-351X |
| Popis: | In ∼50% of prostate cancers, chromosomal rearrangements cause the fusion of the promoter and 5′-UTR of the androgen-regulated TMPRSS2 (transmembrane protease, serine 2) gene to the open reading frame of ERG, encoding an ETS family transcription factor. This fusion results in expression of full-length or N-terminally truncated ERG protein in prostate epithelia. ERG is not expressed in normal prostate epithelia, but when expressed, it promotes tumorigenesis via altered gene expression, stimulating epithelial-mesenchymal transition, cellular migration/invasion, and transformation. However, limited knowledge about the molecular mechanisms of ERG function in prostate cells has hampered efforts to therapeutically target ERG. ERK-mediated phosphorylation of ERG is required for ERG functions in prostate cells, but the reason for this requirement is unknown. Here, we report a mechanism whereby ERK-mediated phosphorylation of ERG at one serine residue causes a conformational change that allows ERK phosphorylation at a second serine residue, Ser-96. We found that the Ser-96 phosphorylation resulted in dissociation of EZH2 and SUZ12, components of polycomb repressive complex 2 (PRC2), transcriptional activation of ERG target genes, and increased cell migration. Conversely, loss of ERG phosphorylation at Ser-96 resulted in recruitment of EZH2 across the ERG-cistrome and a genome-wide loss of ERG-mediated transcriptional activation and cell migration. In conclusion, our findings have identified critical molecular mechanisms involving ERK-mediated ERG activation that could be exploited for therapeutic intervention in ERG-positive prostate cancers. |
| Databáze: | OpenAIRE |
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