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Loss of FOXO1 Cooperates with TMPRSS2-ERG Overexpression to Promote Prostate Tumorigenesis and Cell Invasion.

ABSTRACT: E26 transformation-specific transcription factor ERG is aberrantly overexpressed in approximately 50% of all human prostate cancer due to TMPRSS2-ERG gene rearrangements. However, mice with prostate-specific transgenic expression of prostate cancer-associated ERG alone fail to develop prostate cancer, highlighting that ERG requires other lesions to drive prostate tumorigenesis. Forkhead box (FOXO) transcription factor FOXO1 is a tumor suppressor that is frequently inactivated in human prostate cancer. Here, we demonstrate that FOXO1, but not other FOXO proteins (FOXO3 and FOXO4), binds and inhibits the transcriptional activity of prostate cancer-associated ERG independently of FOXO1 transcriptional activity. Knockdown of endogenous FOXO1 increased invasion of TMPRSS2-ERG fusion-positive VCaP cells, an effect completely abolished by ERG knockdown. Patient specimen analysis demonstrated that FOXO1 and ERG protein expression inversely correlated in a subset of human prostate cancer. Although human ERG transgene expression or homozygous deletion of Foxo1 alone in the mouse prostate failed to promote tumorigenesis, concomitant ERG transgene expression and Foxo1 deletion resulted in upregulation of ERG target genes, increased cell proliferation, and formation of high-grade prostatic intraepithelial neoplasia. Overall, we provide biochemical and genetic evidence that aberrantly activated ERG cooperates with FOXO1 deficiency to promote prostate tumorigenesis and cell invasion. Our findings enhance understanding of prostate cancer etiology and suggest that the FOXO1-ERG signaling axis can be a potential target for treatment of prostate cancer. Cancer Res; 77(23); 6524-37. ©2017 AACR.

SUBMITTER: Yang Y

PROVIDER: S-EPMC5712249 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Loss of FOXO1 Cooperates with TMPRSS2-ERG Overexpression to Promote Prostate Tumorigenesis and Cell Invasion.

Yang Yinhui Y Blee Alexandra M AM Wang Dejie D An Jian J Pan Yunqian Y Yan Yuqian Y Ma Tao T He Yundong Y Dugdale Joseph J Hou Xiaonan X Zhang Jun J Weroha S John SJ Zhu Wei-Guo WG Wang Y Alan YA DePinho Ronald A RA Xu Wanhai W Huang Haojie H

Cancer research 20171006 23

E26 transformation-specific transcription factor ERG is aberrantly overexpressed in approximately 50% of all human prostate cancer due to <i>TMPRSS2-ERG</i> gene rearrangements. However, mice with prostate-specific transgenic expression of prostate cancer-associated ERG alone fail to develop prostate cancer, highlighting that ERG requires other lesions to drive prostate tumorigenesis. Forkhead box (FOXO) transcription factor FOXO1 is a tumor suppressor that is frequently inactivated in human pro ...[more]

PMID: 28986382

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Project description:Gene fusions involving ETS family transcription factors (mainly TMPRSS2-ERG and TMPRSS2-ETV1 fusions) have been found in ~50% of human prostate cancer cases. Although expression of TMPRSS2-ERG or TMPRSS2-ETV1 fusion alone is insufficient to initiate prostate tumorigenesis, they appear to sensitize prostate epithelial cells for cooperation with additional oncogenic mutations to drive frank prostate adenocarcinoma. To search for such ETS-cooperating oncogenic events, we focused on a well-studied prostate tumor suppressor NKX3.1, as loss of NKX3.1 is another common genetic alteration in human prostate cancer. Previous studies have shown that deletions at 8p21 (harboring NKX3.1) and 21q22 (resulting in TMPRSS2-ERG fusion) were both present in a subtype of prostate cancer cases, and that ERG can lead to epigenetic silencing of NKX3.1 in prostate cancer cells, whereas NKX3.1 can in turn negatively regulate TMPRSS2-ERG fusion expression via suppression of the TMPRSS2 promoter activity. We recently generated knockin mouse models for TMPRSS2-ERG and TMPRSS2-ETV1 fusions, utilizing the endogenous Tmprss2 promoter. We crossed these knockin models to an Nkx3.1 knockout mouse model. In Tmprss2-ERG;Nkx3.1+/- (or -/-) male mice, although we observed a slight but significant upregulation of Tmprss2-ERG fusion expression upon Nkx3.1 loss, we did not detect any significant cooperation between these two genetic events to enhance prostate tumorigenesis in vivo. Furthermore, retrospective analysis of a previously published human prostate cancer dataset revealed that within ERG-overexpressing prostate cancer cases, NKX3.1 loss or deletion did not predict biochemical relapse after radical prostatectomy. Collectively, these data suggest that although TMPRSS2-ERG fusion and loss of NKX3.1 are among the most common mutational events found in prostate cancer, and although each of them can sensitize prostate epithelial cells for cooperating with other oncogenic events, these two events themselves do not appear to cooperate at a significant level in vivo to enhance prostate tumorigenesis.

Project description:TMPRSS2-ERG gene fusions that are frequently identified in prostate cancer can be generated either through chromosomal translocation or via interstitial deletion. The latter mechanism deletes an interstitial region of ~3Mb and it remains largely unanswered whether genes deleted within this region contribute to prostate cancer. By characterizing two knockin mouse models recapitulating TMPRSS2-ERG fusions with or without the interstitial deletion, we found that only those with deletion developed poorly differentiated adenocarcinomas with epithelial-to-mesenchymal transition, when under a Pten-null background. We identified several interstitial genes, including ETS2 and BACE2, whose reduced expression correlates with worse disease-free survival and lethal disease. By using an Ets2 conditional knockout allele, we demonstrated that loss of one copy of Ets2 was sufficient for prostate cancer progression when under a Pten-null background. Collectively, our data suggest that ETS2 is a prostate tumor suppressor and haploinsufficiency of one or more interstitial genes contributes to prostate cancer progression. Genotyped male mice were euthanized at 12 months of age and prostates isolated. Prostates were fixed overnight in 10% formalin and stored in 70% ethanol until tissue processing and paraffin embedding. Serial sections were cut from paraffin blocks which were stained for H&E and analyzed by a trained rodent histopathologist. Using these sections as a visual guide for specific types of lesions, the sequential sections were stained with hematoxylin and used for laser capture microdissection on ArcturusXT system. Epithelial cells within notable high grade prostate intraepithelial neoplasia (HG-PIN) lesions were microdissected from 3 mice from each corresponding genotype. In addition, poorly differentiated adenocarcinomas from PbCre;T-3Mb-Erg/+;PtenL/L mice were also dissected. RNA was isolated from the microdissected tissue using the Qiagen RNeasy FFPE kit and subjected to Nugen Amplification before microarray analysis on an Affymetrix Mouse Gene 2.0 ST chip.

Dataset Information

Loss of FOXO1 Cooperates with TMPRSS2-ERG Overexpression to Promote Prostate Tumorigenesis and Cell Invasion.

Publications

Loss of FOXO1 Cooperates with TMPRSS2-ERG Overexpression to Promote Prostate Tumorigenesis and Cell Invasion.

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