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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 HIF1a, 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.
Highlights
SUMO posttranslational modification (PTM) occurs on numerous substrates to affect the protein’s function, subcellular localization, and/or stability
Microarray analysis of prostate tissue isolated from 12-month old SENP1-Tg versus wild-type mice suggested a significant induction of pro-apoptotic genes associated with the canonical AKT/PTEN pathways in the SENP1-Tg mice (Supplementary Figure S1A and S1B)
Since PTEN is a mediator of cellular apoptosis and a target for SUMO-modification, we evaluated the expression of PTEN protein in the prostate of SENP1-Tg mice
Summary
SUMO (small-ubiquitin-like modifier) posttranslational modification (PTM) occurs on numerous substrates to affect the protein’s function, subcellular localization, and/or stability. This PTM is dynamic and the normal kinetics is closely guarded via the activity of SUMO-specific conjugating and deconjugating enzymes. In human PCa cells, SENP1 controls critical mediators of PCa formation and progression the androgen receptor, hypoxia-inducible factor 1a (HIF1α), c-jun, and cyclin D1 [3, 5,6,7]. These observations caused the recent drive www.impactjournals.com/oncotarget to develop SENP1-selective inhibitors [8, 9]. Since SENP1 can and does regulate multiple mechanisms simultaneously, it is highly probable that the absence of carcinoma in the SENP1-Tg mouse model is due to a concurrent SENP1-regulation of unidentified tumor-suppressive pathway(s)
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