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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Nov 30, 2017
- Source ID
- 10.1158/0008-5472.can-17-0686
Entities
People
- Alexandra M. Blee
- Dejie Wang
- Haojie Huang
- Jian An
- Joseph Dugdale
- Jun Zhang
- Ronald A. DePinho
- S. John Weroha
- Tao Ma
- Wanhai Xu
- Wei-guo Zhu
- Xiaonan Hou
- Yanru Wang
- Yinhui Yang
- Yundong He
- Yunqian Pan
- Yuqian Yan
Organizations
- Harbin Medical University
- Mayo Clinic
- Mayo Medical School
- National Institutes of Health
- National Natural Science Foundation of China
- Natural Science Foundation of Heilongjiang Province
- Shenzhen University
- United States Department of Defense
- University of Texas at Austin