SENP1 regulates PTEN stability to dictate prostate cancer development.

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.

SUMO蛋白酶SENP1在包括前列腺癌（PCa）在内的多种癌症中升高。SENP1具有致癌特性；它促进雄激素受体依赖性和非依赖性细胞增殖，稳定HIF1α，增加VEGF，并支持血管生成。然而，表达由雄激素反应性启动子驱动的SENP1转基因（SENP1 - Tg）的小鼠会发展为高级别前列腺上皮内瘤变，但不会发展为癌症。我们现在表明，在SENP1 - Tg中肿瘤抑制性PTEN信号被诱导，以增强前列腺上皮细胞凋亡。SENP1阻断SUMO1依赖性的PTEN泛素化和降解。在没有SENP1的情况下，SUMO1修饰的PTEN被隔离在细胞质中，在那里它与泛素 - E3连接酶WWP2结合。同时，WWP2也被SUMO化，这增强了它与PTEN的相互作用。因此，SENP1引导泛素 - E3 - 底物结合来控制PTEN的稳定性。PTEN作为SENP1介导的前列腺癌发生的屏障，因为只有在PTEN减少后，SENP1 - Tg小鼠才会发展为浸润性癌症。因此，SENP1调节癌症发生的多个方面，并且可能作为侵袭性PTEN缺陷型前列腺癌的特定靶点。