Targeting clinical epigenetic reprogramming for chemoprevention of metabolic and viral hepatocellular carcinoma. Issue 1 (26th March 2020)

• Record Type: Journal Article
• Authors: Jühling, Frank; Hamdane, Nourdine; Crouchet, Emilie; Li, Shen; El Saghire, Houssein; Mukherji, Atish; Fujiwara, Naoto; Oudot, Marine A; Thumann, Christine; Saviano, Antonio; Roca Suarez, Armando Andres; Goto, Kaku; Masia, Ricard; Sojoodi, Mozhdeh; Arora, Gunisha; Aikata, Hiroshi; Ono, Atsushi; Tabrizian, Parissa; Schwartz, Myron; Polyak, Stephen J; Davidson, Irwin; Schmidl, Christian; Bock, Christoph; Schuster, Catherine; Chayama, Kazuaki; Pessaux, Patrick; Tanabe, Kenneth K; Hoshida, Yujin; Zeisel, Mirjam B; Duong, François HT; Fuchs, Bryan C; Baumert, Thomas F;
• Is Part Of: Gut. Volume 70:Issue 1(2021)
• Page Start: 157
• Page End: 169
• Publication Date: 2020-03-26
• Subjects: hepatocellular carcinoma -- gene expression -- hepatitis C -- non-alcoholic steatohepatitis -- chemoprevention; Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gutjnl-2019-318918
• Languages: English
• ISSNs: 0017-5749

Abstract

Abstract : Objective: Hepatocellular carcinoma (HCC) is the fastest-growing cause of cancer-related mortality with chronic viral hepatitis and non-alcoholic steatohepatitis (NASH) as major aetiologies. Treatment options for HCC are unsatisfactory and chemopreventive approaches are absent. Chronic hepatitis C (CHC) results in epigenetic alterations driving HCC risk and persisting following cure. Here, we aimed to investigate epigenetic modifications as targets for liver cancer chemoprevention. Design: Liver tissues from patients with NASH and CHC were analysed by ChIP-Seq (H3K27ac) and RNA-Seq. The liver disease-specific epigenetic and transcriptional reprogramming in patients was modelled in a liver cell culture system. Perturbation studies combined with a targeted small molecule screen followed by i n vivo and ex vivo validation were used to identify chromatin modifiers and readers for HCC chemoprevention. Results: In patients, CHC and NASH share similar epigenetic and transcriptomic modifications driving cancer risk. Using a cell-based system modelling 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 bromodomain 4 inhibited liver disease progression and hepatocarcinogenesis by restoring transcriptional reprogramming of the genes that were epigenetically altered in patients. Conclusion: Our results unravel the functional relevance of metabolic and virus-induced epigenetic alterations for pathogenesis of HCC development and identify chromatin readers as targets for chemoprevention in patients with chronic liver diseases.