USP11 degrades KLF4 via its deubiquitinase activity in liver diseases
Heeyoung Yang1, Daeui Park1,2, Jeongho Ryu1,2
1Department of Predictive Toxicology, Korea Institute of Toxicology, Daejeon, Korea.
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.
Insights
Ubiquitin-specific peptidase 11 (USP11) degrades Krüppel-like factor 4 (KLF4) in liver cancer. USP11 depletion inhibits hepatocellular carcinoma growth and chemoresistance by stabilizing KLF4, offering a potential therapeutic target for liver diseases.
Area of Science:
- Molecular Biology
- Oncology
- Biochemistry
Background:
- Krüppel-like factor 4 (KLF4) functions as a tumor suppressor in hepatocellular carcinoma (HCC), but its regulatory mechanisms are unclear.
- Understanding KLF4 regulation is crucial for developing targeted therapies for liver cancer.
Purpose of the Study:
- To identify proteins interacting with KLF4 and elucidate their role in HCC.
- To investigate the mechanism of KLF4 regulation by USP11 in liver cancer and hepatic steatosis.
Main Methods:
- Proteomic analysis to identify KLF4-interacting proteins.
- Biochemical assays to determine USP11's deubiquitinating activity on KLF4.
- Cell-based assays to assess the impact of USP11 depletion on HCC cell growth, chemoresistance, and lipid metabolism.
- Analysis of clinical data from HCC and non-alcoholic fatty liver disease patients.
Main Results:
- USP11 was identified as a KLF4-interacting deubiquitinating enzyme.
- USP11 promotes KLF4 degradation via K63-linked polyubiquitination, inhibiting KLF4 expression.
- USP11 depletion enhances KLF4 stability, suppressing HCC cell growth and chemoresistance.
- USP11 knockout reduced lipid content and fatty acid metabolism gene expression in vitro.
- Elevated USP11 and reduced KLF4 levels correlate with hepatic steatosis and HCC in clinical data.
Conclusions:
- USP11 deubiquitinates and destabilizes KLF4, contributing to hepatic tumorigenesis.
- USP11 inhibition represents a potential therapeutic strategy for liver diseases, including HCC and non-alcoholic fatty liver disease.
- Targeting USP11 may restore KLF4 function and improve treatment outcomes.
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