RESUMEN
The TMPRSS2/ERG gene rearrangement occurs in 50% of prostate tumors and results in expression of the transcription factor ERG, which is normally silent in prostate cells. ERG expression promotes prostate tumor formation and luminal epithelial cell fates when combined with PI3K/AKT pathway activation, however the mechanism of synergy is not known. In contrast to luminal fates, expression of ERG alone in immortalized normal prostate epithelial cells promotes cell migration and epithelial to mesenchymal transition (EMT). Migration requires ERG serine 96 phosphorylation via endogenous Ras/ERK signaling. We found that a phosphomimetic mutant, S96E ERG, drove tumor formation and clonogenic survival without activated AKT. S96 was only phosphorylated on nuclear ERG, and differential recruitment of ERK to a subset of ERG-bound chromatin associated with ERG-activated, but not ERG-repressed genes. S96E did not alter ERG genomic binding, but caused a loss of ERG-mediated repression, EZH2 binding and H3K27 methylation. In contrast, AKT activation altered the ERG cistrome and promoted expression of luminal cell fate genes. These data suggest that, depending on AKT status, ERG can promote either luminal or EMT transcription programs, but ERG can promote tumorigenesis independent of these cell fates and tumorigenesis requires only the transcriptional activation function.
Asunto(s)
Regulación Neoplásica de la Expresión Génica/genética , Neoplasias de la Próstata/metabolismo , Animales , Carcinogénesis/genética , Línea Celular Tumoral , Movimiento Celular/fisiología , Transformación Celular Neoplásica/genética , Transición Epitelial-Mesenquimal , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Expresión Génica/genética , Regulación Neoplásica de la Expresión Génica/fisiología , Genes Reguladores , Xenoinjertos , Humanos , Sistema de Señalización de MAP Quinasas/genética , Masculino , Ratones , Ratones Desnudos , Fosfatidilinositol 3-Quinasas/genética , Próstata/patología , Neoplasias de la Próstata/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/genética , Factores de Transcripción/genética , Activación Transcripcional , Regulador Transcripcional ERG/genética , Regulador Transcripcional ERG/metabolismo , Proteínas ras/metabolismoRESUMEN
Prostate cancer is unique among carcinomas in that a fusion gene created by a chromosomal rearrangement is a common driver of the disease. The TMPRSS2/ERG rearrangement drives aberrant expression of the ETS family transcription factor ERG in 50% of prostate tumors. Similar rearrangements promote aberrant expression of the ETS family transcription factors ETV1 and ETV4 in another 10% of cases. Together, these three ETS factors are thought to promote tumorigenesis in the majority of prostate cancers. A goal of precision medicine is to be able to apply targeted therapeutics that are specific to disease subtypes. ETS gene rearrangement positive tumors represent the largest molecular subtype of prostate cancer, but to date there is no treatment specific to this marker. In this chapter we will review the latest findings regarding the molecular mechanisms of ETS factor function in the prostate. These molecular details may provide a path towards new therapeutic targets for this subtype of prostate cancer. Further, we will describe efforts to target the oncogenic functions of ETS family transcription factors directly as well as indirectly.
Asunto(s)
Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Proteínas Proto-Oncogénicas c-ets/metabolismo , Regulador Transcripcional ERG/metabolismo , Aberraciones Cromosómicas , Humanos , Masculino , Oncogenes/genética , Neoplasias de la Próstata/patología , Recombinación Genética/genéticaRESUMEN
In â¼50% 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.