Ubiquitin-specific protease 35 (USP35) is a member of the ubiquitin-specific protease family (USP), which influences the progression of multiple cancers by deubiquitinating a variety of substrates. In recent years, the specific role of USP35 was begun to be understood. In this study, we investigated the role and underlying molecular mechanisms of USP35 in chemoresistance of non-small cell lung cancer (NSCLC) to cisplatin. Depletion of USP35 increased the sensitivity of NSCLC to cisplatin-induced apoptosis. We screened and identified a potential substrate of USP35, baculoviral IAP repeat containing 3 (BIRC3). Overexpression of USP35 in H460 cells increased the abundance of BIRC3, while USP35 knockdown in Anip973 cells decreased BIRC3 abundance. Notably, USP35 directly interacted with and stabilized BIRC3 through lys48-mediated polyubiquitination via its deubiquitinating enzyme activity. USP35 alleviated cisplatin-induced cell apoptosis by regulating BIRC3 levels in NSCLC cells. Moreover, a significant positive correlation between USP35 and BIRC3 protein expression levels was observed in human NSCLC tissues. Taken together, USP35 plays a vital role in resistance to cisplatin-induced cell death through the overexpression of BIRC3. USP35 might be a potentially novel therapeutic target in human NSCLC.
© 2022. The Author(s), under exclusive licence to United States and Canadian Academy of Pathology.