The role of the deubiquitinase CYLD for liver injury and hepatocarcinogenesis

• Applicant: Professor Dr. Henning Schulze-Bergkamen
• Subject Area: Gastroenterology ; Hematology, Oncology ; Cell Biology
• Term: from 2014 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 260436363

CYLD is a deubiquitinating enzyme that removes K63-linked ubiquitin chains from target proteins, e.g. involved in NF-kB, Wnt/ß-catenin and BCL-3 signalling pathways. Loss of CYLD expression has been observed in different types of human cancer. Together with decreased levels of CYLD expression in human hepatocellular carcinoma (HCC), we have demonstrated spontaneous chronic liver injury and increased carcinogen-induced HCC in a murine CYLD knockout model, lacking full length CYLD, but expressing a naturally occurring splice variant (CYLDex7/8 xAlbCre). The aim of the project is to unravel the mechanisms of liver injury and hepatocarcinogenesis caused by reduced CYLD activity and to analyse approaches to sensitize HCC to therapy-induced cell death by manipulating CYLD. Specifically, we will analyse HCC development in murine CYLD knockout models which differ regarding expression of splice variants. This will help to clarify whether the lack of full length CYLD or the expression of splice variants is pivotal for HCC development in mice. Target proteins undergoing CYLD-mediated deubiquitination in hepatocytes, will be identified. Since we observed increased activity of the NF-kB family member RelB as well as the protooncogene BCL-3 in CYLDex7/8 xAlbCre mice, we will analyse liver injury and HCC development in hepatocyte-specific double knockouts of CYLD and BCL-3 or RelB. As we have evidence that CYLD critically regulates apoptosis signalling in murine hepatocytes and may thereby influence hepatocarcinogenesis, signalling events contributing to increased resistance of CYLD-negative hepatocytes towards death-receptor mediated apoptosis will be explored. We will also further specify, how decreased CYLD expression contributes to the resistance of human HCC cells towards targeted agents, such as sorafenib and c-MET inhibitors. In addition, we plan to identify ways to trigger CYLD expression in HCC cells and vital tissue cultures of human HCC to further develop translational efforts for HCC treatment. We believe that reconstitution of CYLD is a promising approach for the treatment of chronic liver diseases and the sensitization of HCC cells towards therapy-induced cell death.

• DFG Programme: Research Grants