Role of SENP1 in Prostate Cancer Pathogenesis

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DESCRIPTION (provided by applicant): Our laboratory cloned the first human sentrin/SUMO-specific protease, SENP1. The isopeptidase activity of this enzyme deconjugates the posttranslation modification by SUMO (small ubiquitin-like modifier). Although its catalytic activity has been characterized, the biological significance of SENP1 remains unknown. Recently we observed that SENP1 enhances androgen receptor (AR)-dependent transcription. Numerous reports conclude that enhancement of AR activity promotes development of prostate cancer (PCa), the most frequently diagnosed carcinoma in males. In situ hybridization studies indicate an overexpression of SENP1 in pre-cancer and cancer lesions, but not normal prostate epithelia. Also, stable overexpression of SENP1 prompts PCa cell growth and transformation. Currently, it is unknown whether enhanced expression of SENP1 promotes prostate carcinogenesis; hence we propose to test whether induction of SENP1 regulates the development and progression of prostate cancer. Using an inducible system, the effect of SENP1 expression on proliferation of LNCaP cells and tumor growth in nude mice will be explored. Also, transgenic mice overexpressing SENP1 in the prostate will be evaluated for tumor formation and aggressiveness.