USP54 suppresses bladder cancer proliferation, stemness, and cisplatin resistance via deubiquitination-mediated stabilization of SIRT6

Bladder cancer is a prevalent and lethal malignancy worldwide, with treatment options often limited by the development of chemoresistance, especially to cisplatin-based regimens. In this study, we identified ubiquitin-specific protease 54 (USP54) as a novel regulator of bladder cancer cell proliferation, stemness, and cisplatin resistance. USP54 expression was consistently downregulated in both clinical bladder cancer specimens and cell lines. Functional experiments demonstrated that USP54 overexpression inhibited cancer cell growth, attenuated CSC-like properties, and restored cisplatin sensitivity in resistant cells by promoting drug-induced apoptosis. Mechanistically, USP54 directly interacted with SIRT6 and facilitated its deubiquitination, leading to increased SIRT6 protein stability. This post-translational stabilization of SIRT6 was shown to mediate the tumor-suppressive functions of USP54 in bladder cancer progression and chemoresistance. Together, these results uncover the USP54-SIRT6 axis as a previously unrecognized regulatory pathway controlling stemness and cisplatin response in bladder cancer.