Abstract
Krüppel-like factor 4 (KLF4) is a zinc-finger containing DNA-binding transcription factor involved in tumorigenesis and acts as a tumour suppressor or an oncogene depending on the tissue. In hepatocellular carcinoma (HCC), KLF4 has been considered as a tumour suppressor, although the mechanism underlying its action remains largely unknown. In this study, we identified the ubiquitin-specific peptidase USP11 as a KLF4-interacting deubiquitinating enzyme using a proteomic approach. USP11 destabilizes KLF4 through the removal of K63-dependent polyubiquitination, thereby inhibiting KLF4 expression. We also provide mechanistic insights into KLF4 degradation and show that USP11 depletion inhibits growth and chemoresistance of HCC cells by enhancing KLF4 stability. Importantly, lipid content was reduced and genes involved in fatty acid metabolism were down-regulated in an in vitro steatosis conditions upon USP11 knockout. Finally, elevated USP11 and reduced KLF4 levels were detected both in a hepatic steatosis in vitro model and in public clinical data of non-alcoholic fatty liver disease and HCC patients. Collectively, these findings suggest that USP11, as KLF4-binding partner, is an important mediator of hepatic tumorigenesis that functions via degradation of KLF4 and is a potential treatment target for liver diseases.