Phosphorylation of the oncogenic transcription factor ERG in prostate cells dissociates polycomb repressive complex 2, allowing target gene activation

• Published in: The Journal of biological chemistry 2017-10, Vol.292 (42), p.17225-17235
• Main Authors: Kedage, Vivekananda, Strittmatter, Brady G., Dausinas, Paige B., Hollenhorst, Peter C.
• Format: Article
• Language: English
• Subjects: Cell Line; ETS transcription factor family; Extracellular Signal-Regulated MAP Kinases - genetics; Extracellular Signal-Regulated MAP Kinases - metabolism; Gene Expression Regulation, Neoplastic; Gene Regulation; Humans; Male; mitogen-activated protein kinase (MAPK); Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Phosphorylation - genetics; polycomb; Polycomb Repressive Complex 2 - genetics; Polycomb Repressive Complex 2 - metabolism; Prostate - metabolism; Prostate - pathology; prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; transcription factor; Transcriptional Activation; Transcriptional Regulator ERG - genetics; Transcriptional Regulator ERG - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M117.796458

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.