Journal Article

ERF mutations reveal a balance of ETS factors controlling prostate oncogenesis

Schultz, Nikolaus, Sawyers, Charles L., Wongvipat, John, Zhao, Yilin, Bose, Rohit, Armenia, Joshua, Abida, Wassim, Zheng, Deyou, Wang, Ping, Karthaus, Wouter R., Iaquinta, Phillip J., Sullivan, Patrick S., Patruno, Anna, Zhang, Zeda, Shah, Neel, Doran, Michael G., Wasmuth, Elizabeth V.

2017

Overview

In prostate cancer, the oncogenicity of transcription factor ERG is mediated, in part, by competition with another member of the ETS family, ERF. Opposing protein actions in tumour growth In prostate cancer, TMPRSS2 – ERG translocations are very frequent and lead to overexpression of ERG, which can trigger tumour growth. Rohit Bose and colleagues now show that another member of the ETS family, ERF, functions as a tumour suppressor in prostate cancer. ERF is lost in many tumours without TMPRSS2 – ERG translocations. ERF normally competes with other members of the ETS family for binding to DNA, and this function is disabled either by loss of ERF or increased levels of ERG. These findings shed further light on the opposing functions of ETS family proteins in tumorigenesis. 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 1 , 2 . Recent genomic landscape studies of such cancers 3 , 4 , 5 , 6 , 7 , 8 have reported recurrent point mutations and focal deletions of another ETS member, the ETS2 repressor factor ERF 9 . 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 38/15 / 38/91 / 631/67/1244 / 631/67/589/466 / Androgen receptors / Androgens / Androgens - metabolism / Animals / Carcinogenesis - genetics / Cell Line, Tumor / Chromatin / Deoxyribonucleic acid / DNA / DNA sequencing / ETS protein / Ets-2 protein / Gene mutation / Genes / Genes - genetics / Genetic aspects / Genotype & phenotype / Health aspects / Humanities and Social Sciences / Humans / Immunoprecipitation / Landscape studies / letter / Male / Medical research / Metastasis / Mice / Morphology / multidisciplinary / Mutation / Oncology / Pathology / Prostate - metabolism / Prostate - pathology / Prostate cancer / Prostatic Neoplasms - genetics / Prostatic Neoplasms - pathology / Protein Stability / Proto-Oncogene Proteins c-ets - metabolism / PTEN protein / Receptors, Androgen - metabolism / Repressor Proteins - deficiency / Repressor Proteins - genetics / Repressor Proteins - metabolism / Science / Serine Endopeptidases - deficiency / Serine Endopeptidases - metabolism / Signal Transduction / Suppressors / Transcription factors / Transcriptional Regulator ERG - deficiency / Transcriptional Regulator ERG - metabolism / Transcriptome - genetics / Tumor Suppressor Proteins - metabolism / Tumorigenesis / Tumors / Up-Regulation / Urology