Ras/ERK and PI3K/AKT signaling differentially regulate oncogenic ERG mediated transcription in prostate cells.

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...

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Autores principales:	Brady G Strittmatter, Travis J Jerde, Peter C Hollenhorst
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Genetics QH426-470
Acceso en línea:	https://doaj.org/article/afec4a57568441b48b49b4d306cf744d
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spelling	oai:doaj.org-article:afec4a57568441b48b49b4d306cf744d2021-12-02T20:02:55ZRas/ERK and PI3K/AKT signaling differentially regulate oncogenic ERG mediated transcription in prostate cells.1553-73901553-740410.1371/journal.pgen.1009708https://doaj.org/article/afec4a57568441b48b49b4d306cf744d2021-07-01T00:00:00Zhttps://doi.org/10.1371/journal.pgen.1009708https://doaj.org/toc/1553-7390https://doaj.org/toc/1553-7404The 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.Brady G StrittmatterTravis J JerdePeter C HollenhorstPublic Library of Science (PLoS)articleGeneticsQH426-470ENPLoS Genetics, Vol 17, Iss 7, p e1009708 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Genetics QH426-470
spellingShingle	Genetics QH426-470 Brady G Strittmatter Travis J Jerde Peter C Hollenhorst Ras/ERK and PI3K/AKT signaling differentially regulate oncogenic ERG mediated transcription in prostate cells.
description	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.
format	article
author	Brady G Strittmatter Travis J Jerde Peter C Hollenhorst
author_facet	Brady G Strittmatter Travis J Jerde Peter C Hollenhorst
author_sort	Brady G Strittmatter
title	Ras/ERK and PI3K/AKT signaling differentially regulate oncogenic ERG mediated transcription in prostate cells.
title_short	Ras/ERK and PI3K/AKT signaling differentially regulate oncogenic ERG mediated transcription in prostate cells.
title_full	Ras/ERK and PI3K/AKT signaling differentially regulate oncogenic ERG mediated transcription in prostate cells.
title_fullStr	Ras/ERK and PI3K/AKT signaling differentially regulate oncogenic ERG mediated transcription in prostate cells.
title_full_unstemmed	Ras/ERK and PI3K/AKT signaling differentially regulate oncogenic ERG mediated transcription in prostate cells.
title_sort	ras/erk and pi3k/akt signaling differentially regulate oncogenic erg mediated transcription in prostate cells.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/afec4a57568441b48b49b4d306cf744d
work_keys_str_mv	AT bradygstrittmatter raserkandpi3kaktsignalingdifferentiallyregulateoncogenicergmediatedtranscriptioninprostatecells AT travisjjerde raserkandpi3kaktsignalingdifferentiallyregulateoncogenicergmediatedtranscriptioninprostatecells AT peterchollenhorst raserkandpi3kaktsignalingdifferentiallyregulateoncogenicergmediatedtranscriptioninprostatecells
_version_	1718375680149815296

Ras/ERK and PI3K/AKT signaling differentially regulate oncogenic ERG mediated transcription in prostate cells.

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