SENP1 regulates PTEN stability to dictate prostate cancer development
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Tasneem Bawa-Khalfe1, Feng-Ming Yang2, Joan Ritho2, Hui-Kuan Lin3,4, Jinke Cheng5,6 and Edward T.H. Yeh2
1 Department of Biology & Biochemistry, Center for Nuclear Receptors & Cell Signaling, University of Houston, Houston, Texas, USA
2 Department of Internal Medicine, The University of Missouri, Columbia, MO, USA
3 Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
4 Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
5 Department of Biochemistry and Molecular Cell Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China
6 State Key Laboratory of Oncogenes & Related Genes, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Tasneem Bawa-Khalfe, email:
Edward T.H. Yeh, email:
Keywords: SENP1, PTEN, WWP2, SUMO, prostate carcinogenesis
Received: May 27, 2016 Accepted: November 07, 2016 Published: November 10, 2016
SUMO protease SENP1 is elevated in multiple carcinomas including prostate cancer (PCa). SENP1 exhibits carcinogenic properties; it promotes androgen receptor-dependent and -independent cell proliferation, stabilizes HIF1α, increases VEGF, and supports angiogenesis. However, mice expressing an androgen-responsive promoter driven SENP1-transgene (SENP1-Tg) develop high-grade prostatic intraepithelial neoplasia, but not carcinoma. We now show that tumor suppressive PTEN signaling is induced in SENP1-Tg to enhance prostate epithelial cell apoptosis. SENP1 blocks SUMO1-dependent ubiquitylation and degradation of PTEN. In the absence of SENP1, SUMO1-modified PTEN is sequestered in the cytosol, where binding to ubiquitin-E3 ligase WWP2 occurs. Concurrently, WWP2 is also SUMOylated, which potentiates its interaction with PTEN. Thus, SENP1 directs ubiquitin-E3-substrate association to control PTEN stability. PTEN serves as a barrier for SENP1-mediated prostate carcinogenesis as SENP1-Tg mice develop invasive carcinomas only after PTEN reduction. Hence, SENP1 modulates multiple facets of carcinogenesis and may serve as a target specifically for aggressive PTEN-deficient PCa.
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Edward T.H. Yeh
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