SENP1 regulates PTEN stability to dictate prostate cancer development

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

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

SUMO protease SENP1 is elevated in multiple carcinomas including prostate cancer (PCa). SENP1 exhibits carcinogenic properties; it promotes androgen receptordependent 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.

Original languageEnglish
Pages (from-to)17651-17664
Number of pages14
JournalOncotarget
Volume8
Issue number11
DOIs
Publication statusPublished - Jan 1 2017
Externally publishedYes

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Keywords

  • Prostate carcinogenesis
  • PTEN
  • SENP1
  • SUMO
  • WWP2

ASJC Scopus subject areas

  • Oncology

Cite this

Bawa-Khalfe, T., Yang, F. M., Ritho, J., Lin, H. K., Cheng, J., & Yeh, E. T. H. (2017). SENP1 regulates PTEN stability to dictate prostate cancer development. Oncotarget, 8(11), 17651-17664. https://doi.org/10.18632/oncotarget.13283