DUB3/KLF4 Combats Tumor Growth and Chemoresistance in Hepatocellular Carcinoma

This study aimed to investigate the role of deubiquitinating enzyme 3 (DUB3) in the regulation of Krüppel-like factor 4 (KLF4) expression in hepatocellular carcinoma (HCC). Gain- and loss-of-function assay, luciferase reporter assay, co-immunoprecipitation, and intracellular and extracellular deubiquitination assays were conducted in vitro. A tumor xenograft mouse model was established. The expression of DUB3 and KLF4 was examined in HCC patient specimens. The results showed that DUB3 upregulated KLF4 expression by deubiquitinating and stabilizing KLF4 protein in HCC cells through binding with KLF4. DUB3 inhibited HCC cell proliferation in vitro and tumor growth in vivo while enhancing the chemosensitivity of HCC cells in a KLF4-dependent manner. Furthermore, KLF4 promoted DUB3 transcription by binding to the DUB3 promoter. In HCC patients, DUB3 expression positively correlated with KLF4 expression in HCC tissues. Low DUB3 expression predicted worse overall survival and recurrence in HCC patients. In conclusion, this study revealed a positive DUB3/KLF4 feedback loop that inhibits tumor growth and chemoresistance in HCC. These results suggest that DUB3/KLF4 activation might be a potential therapeutic approach for HCC treatment.