Oncotarget

Research Papers:

SENP1 regulates PTEN stability to dictate prostate cancer development

Tasneem Bawa-Khalfe _, Feng-Ming Yang, Joan Ritho, Hui-Kuan Lin, Jinke Cheng and Edward T.H. Yeh

PDF  |  HTML  |  Supplementary Files  |  How to cite

Oncotarget. 2017; 8:17651-17664. https://doi.org/10.18632/oncotarget.13283

Metrics: PDF 2941 views  |   HTML 2692 views  |   ?  


Abstract

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

Correspondence to:

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

Abstract

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.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.
PII: 13283