OTUB1 facilitates bladder cancer progression by stabilizing ATF6 in response to ER stress.

The unfolded protein response (UPR) plays an important role in carcinogenesis, but the functional role and mechanism of UPR-associated bladder carcinogenesis remain to be characterized. Upon UPR activation, ATF6α is activated to upregulate the transcription of UPR target genes. Although the mechanism of ATF6 activation has been studied extensively, the negative regulation of ATF6 stabilization is not well understood. Here, we report that the deubiquitinase otubain 1 (OTUB1) facilitates bladder cancer progression by stabilizing ATF6 in response to ER stress. OTUB1 expression is elevated in bladder cancer patients. Genetic ablation of OTUB1 markedly inhibited bladder cancer cell proliferation, viability and migration both in vitro and in vivo. Mechanistically, luciferase pathway screening showed that ATF6 signaling was clearly activated compared to other pathways. OTUB1 was found to activate ATF6 signaling by inhibiting its ubiquitylation, thereby remodeling the stressed cells through transcriptional regulation. Our results indicate that high OTUB1 expression promotes bladder cancer progression by stabilizing ATF6 and that OTUB1 is a potential therapeutic target in bladder cancer.