USP35 Promotes Malignant Subtype Transition of Bladder Cancer Cells

ZHOU Zijing¹*, GUO Yadong², SHAN Zezhi³, MAO Shiyu², ZHENG Zening², GE Xin²

(¹School of Medicine, Anhui University of Science and Technology, Huainan 232001, China;²School of Medicine, Tongji University/Shanghai Tenth People’s Hospital Affiliated to Tongji University, Shanghai 200092, China;³Department of Internal Medicine, Fudan University Shanghai Cancer Hospital, Shanghai 200030, China)

Abstract:

The malignant subtype transition of BCa (bladder cancer) cells is the transition from non-muscle invasive bladder cancer to muscle invasive bladder cancer, which is detrimental to bladder cancer patients. EMT (epithelial-mesenchymal transition) is reported to possess the most positive correlation with this transition. However, the underlying mechanism is still elusive although EMT-related gene signature have been shown to be prognostic indicators and potential therapeutic targets for cancer. This study found that the deubiquitinase USP35 altered the protein stability of multiple EMT-related factors. USP35 played a clear evident role in downregulation of Ecadherin and P53, together with upregulation of N-cadherin. Simultaneously, TargetScan analysis found that almost half of USP35-related miRNAs were also involved in MDM2 mediated post-transcriptional regulation. So USP35 may trigger MDM2 upregulation through miRNA competition, resulting in P53 downregulation, and MDM2 forms a complete negative feedback loop with P53. Furthermore, knockdown USP35 inhibits EMT-induced proliferation and migration capability of BCa cells, suggesting that the up-regulation of USP35 may serve as a foundational signal for BCa transition to malignant phenotype.

CSTR: 32200.14.cjcb.2023.06.0003