Targeting clinical epigenetic reprogramming for chemoprevention of metabolic and viral hepatocellular carcinoma

Chronic hepatitis C (CHC) and non-alcoholic steatohepatitis (NASH) are major underlying etiologies for hepatocellular carcinoma (HCC), one of the fastest growing cause for cancer-related mortality. However, options for treating HCC are unsatisfactory with absent chemopreventive strategies. Here, we aimed to investigate hepatocyte chromatin readers and modifiers as targets for HCC chemoprevention in CHC- and NASH-induced liver disease. Liver tissues samples from CHC and NASH patients with early and late stage disease were analyzed using genome-wide RNA-seq and ChIPmentation-based ChIP-Seq of the H3K27ac histone modification. CHC- and NASH-specific epigenetic modifications and transcriptional reprogramming were modeled in human liver cell culture systems and animal models. Perturbation studies combined with small molecule screens followed by in vivo and ex vivo validation were applied to identify chromatin modifiers and readers for HCC chemoprevention. CHC and NASH share a redundant set of epigenetic and transcriptional modifications inducing a transcriptional program driving carcinogenesis in the liver of patients. Using a cell-based system modeling the virus and NASH-induced epigenetic modifications in patients, we identified chromatin readers as targets to revert liver gene transcription driving clinical HCC risk. Proof-of-concept studies in a NASH-HCC mouse model showed that the pharmacological inhibition of chromatin reader BRD4 inhibited liver disease progression and hepatocarcinogenesis by restoring transcriptional reprogramming of the genes that were epigenetically altered in patients. Our epigenetic and transcriptional analyses suggest that CHC and NASH share common mechanisms of disease progression and HCC risk. Our perturbation studies in cell culture and animal models uncover the functional relevance of metabolic and virus-induced epigenetic alterations for HCC risk. Our pharmacological in vivo studies identify chromatin readers are candidate targets for HCC chemoprevention in patients with chronic liver disease.