Identification of SERTAD1 Oncoprotein as a Novel USP15-interacting Protein Regulated by USP15 and SIAH1 in Ovarian Cancer

Abstract

Ubiquitin-specific protease 15 (USP15), a member of the deubiquitylating enzyme (DUB) family, reportedly stabilizes several important oncoprotein substrates and is also reportedly up-regulated in ovarian cancers. In this study, we identified SERTA-containing domain 1 (SERTAD1) as a novel interacting protein with USP15 using yeast-two hybrid analysis. SERTAD1 is reportedly overexpressed in ovarian cancer cells and induces chromosome instability, cancer cell survival, and exhibits anti-apoptotic effects. Our study showed that overexpression of USP15 results in increased levels of SERTAD1 protein, and knockdown of USP15 using small interfering RNA decreased SERTAD1 protein levels in ovarian cancer cell lines. The catalytically inactive form of USP15 exhibited a decreased stabilizing effect on SERTAD1. These results suggest that USP15 directly regulates SERTAD1 protein levels via USP15-mediated DUB enzymatic activity in ovarian cancers. Moreover, we found that SERTAD1 expression was decreased by SIAH1, and reduced SIAH1 protein levels are frequently found in ovarian cancers. Our results indicate that USP15 overexpression and reduced SIAH1 levels induce SERTAD1 overexpression to promote carcinogenesis in human ovarian cancer.