c‐Rel–dependent Chk2 signaling regulates the DNA damage response limiting hepatocarcinogenesis

• DOI: 10.1002/hep.32781
• Publication Date: 2022-09-12T01:09:50Z
• Authors: Jack Leslie; Jill E. Hunter; Amy Collins; Amelia Rushton; Lauren G. Russell; Erik Ramon‐Gil; Maja Laszczewska; Misti McCain; Marco Y. W. Zaki; Amber Knox; Yixin Seow; Laura Sabater; Daniel Geh; Neil D. Perkins; Helen L. Reeves; Dina Tiniakos; Derek A. Mann; Fiona Oakley
• Keywords: 0301 basic medicine; Cancer Research; Carcinoma, Hepatocellular; Original Articles: Liver Cancer; Carcinogenesis; Physiology; Hepatocellular carcinoma; DNA repair; Apoptosis; Cancer research; Gene; Mice; Cell growth; 03 medical and health sciences; Biochemistry, Genetics and Molecular Biology; Role of Nrf2 Signaling in Oxidative Stress Response; Genetics; Animals; Humans; Chemotherapy; Molecular Biology; Biology; Cancer; Programmed cell death; Mice, Knockout; 0303 health sciences; Molecular Physiology of Purinergic Signalling; Liver Neoplasms; NF-kappa B; Life Sciences; DNA; Proto-Oncogene Proteins c-rel; 3. Good health; Doxorubicin; FOS: Biological sciences; Hepatocytes; DNA damage; Nucleotide Signalling; NF-?B Signaling in Inflammation and Cancer; Transcription factor; DNA Damage

Background and Aims: Hepatocellular carcinoma (HCC) is a leading cause of cancer‐related death. The NF‐κB transcription factor family subunit c‐Rel is typically protumorigenic; however, it has recently been reported as a tumor suppressor. Here, we investigated the role of c‐Rel in HCC.

Approach and Results: Histological and transcriptional studies confirmed expression of c‐Rel in human patients with HCC, but low c‐Rel expression correlated with increased tumor cell proliferation and mutational burden and was associated with advanced disease. In vivo, global (Rel

−/− ) and epithelial specific (Rel

Alb ) c‐Rel knockout mice develop more tumors, with a higher proliferative rate and increased DNA damage, than wild‐type (WT) controls 30 weeks after N‐diethylnitrosamine injury. However, tumor burden was comparable when c‐Rel was deleted in hepatocytes once tumors were established, suggesting c‐Rel signaling is important for preventing HCC initiation after genotoxic injury, rather than for HCC progression. In vitro, Rel

−/− hepatocytes were more susceptible to genotoxic injury than WT controls. ATM‐CHK2 DNA damage response pathway proteins were suppressed in Rel

−/− hepatocytes following genotoxic injury, suggesting that c‐Rel is required for effective DNA repair. To determine if c‐Rel inhibition sensitizes cancer cells to chemotherapy, by preventing repair of chemotherapy‐induced DNA damage, thus increasing tumor cell death, we administered single or combination doxorubicin and IT‐603 (c‐Rel inhibitor) therapy in an orthotopic HCC model. Indeed, combination therapy was more efficacious than doxorubicin alone.

Conclusion: Hepatocyte c‐Rel signaling limits genotoxic injury and subsequent HCC burden. Inhibiting c‐Rel as an adjuvant therapy increased the effectiveness of DNA damaging agents and reduced HCC growth.