title: SENP1 regulates PTEN stability to dictate prostate cancer development.
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.
authors.affiliation: Department of Biology & Biochemistry, Center for Nuclear Receptors & Cell Signaling, University of Houston, Houston, Texas, USA.
authors.forename: Tasneem
authors.initials: T
authors.lastname: Bawa-Khalfe
authors.affiliation: Department of Internal Medicine, The University of Missouri, Columbia, MO, USA.
authors.forename: Feng-Ming
authors.initials: FM
authors.lastname: Yang
authors.affiliation: Department of Internal Medicine, The University of Missouri, Columbia, MO, USA.
authors.forename: Joan
authors.initials: J
authors.lastname: Ritho
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.|Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
authors.forename: Hui-Kuan
authors.initials: HK
authors.lastname: Lin
authors.affiliation: 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.|State Key Laboratory of Oncogenes & Related Genes, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Jinke
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Department of Internal Medicine, The University of Missouri, Columbia, MO, USA.
authors.forename: Edward T H
authors.initials: ET
authors.lastname: Yeh
mesh_terms: D000818:Animals; D017209:Apoptosis; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology*; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D004195:Disease Models, Animal; D010450:Endopeptidases / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D055550:Protein Stability
chemical_list: D051059:PTEN Phosphohydrolase; D010450:Endopeptidases; C404512:SENP1 protein, human; D003546:Cysteine Endopeptidases; C501974:Senp1 protein, mouse
keywords: PTEN; SENP1; SUMO; WWP2; prostate carcinogenesis