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Nature. 2017 Jun 29;546(7660):671-675. doi: 10.1038/nature22820. Epub 2017 Jun 14.

ERF mutations reveal a balance of ETS factors controlling prostate oncogenesis.

Author information

1
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA.
2
Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA.
3
Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA.
4
Louis V. Gerstner, Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
5
Department of Genetics, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
6
Department of Neurology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
7
Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
8
Howard Hughes Medical Institute, Chevy Chase, Maryland 20185, USA.

Abstract

Half of all prostate cancers are caused by the TMPRSS2-ERG gene-fusion, which enables androgens to drive expression of the normally silent E26 transformation-specific (ETS) transcription factor ERG in prostate cells. Recent genomic landscape studies of such cancers have reported recurrent point mutations and focal deletions of another ETS member, the ETS2 repressor factor ERF. Here we show these ERF mutations cause decreased protein stability and mostly occur in tumours without ERG upregulation. ERF loss recapitulates the morphological and phenotypic features of ERG gain in normal mouse prostate cells, including expansion of the androgen receptor transcriptional repertoire, and ERF has tumour suppressor activity in the same genetic background of Pten loss that yields oncogenic activity by ERG. In the more common scenario of ERG upregulation, chromatin immunoprecipitation followed by sequencing indicates that ERG inhibits the ability of ERF to bind DNA at consensus ETS sites both in normal and in cancerous prostate cells. Consistent with a competition model, ERF overexpression blocks ERG-dependent tumour growth, and ERF loss rescues TMPRSS2-ERG-positive prostate cancer cells from ERG dependency. Collectively, these data provide evidence that the oncogenicity of ERG is mediated, in part, by competition with ERF and they raise the larger question of whether other gain-of-function oncogenic transcription factors might also inactivate endogenous tumour suppressors.

PMID:
28614298
PMCID:
PMC5576182
DOI:
10.1038/nature22820
[Indexed for MEDLINE]
Free PMC Article

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