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

Frank Jühling, Nourdine Hamdane, Emilie Crouchet, Shen Li, Houssein El Saghire, Atish Mukherji, Naoto Fujiwara, Marine A. Oudot, Christine Thumann, Antonio Saviano, Armando Andres Roca Suarez, Kaku Goto, Ricard Masia, Mozhdeh Sojoodi, Gunisha Arora, Hiroshi Aikata, Atsushi Ono, Parissa Tabrizian, Myron Schwartz, Stephen J. PolyakIrwin Davidson, Christian Schmidl, Christoph Bock, Catherine Schuster, Kazuaki Chayama, Patrick Pessaux, Kenneth K. Tanabe, Yujin Hoshida, Mirjam B. Zeisel, François H.T. Duong, Bryan C. Fuchs, Thomas F. Baumert

Research output: Contribution to journalArticle

1 Scopus citations

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 in 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.

Original languageEnglish (US)
Article number318918
JournalGut
DOIs
StateAccepted/In press - 2020

Keywords

  • Hepatocellular carcinoma
  • chemoprevention
  • gene expression
  • hepatitis C
  • non-alcoholic steatohepatitis

ASJC Scopus subject areas

  • Gastroenterology

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    Jühling, F., Hamdane, N., Crouchet, E., Li, S., El Saghire, H., Mukherji, A., Fujiwara, N., Oudot, M. A., Thumann, C., Saviano, A., Roca Suarez, A. A., Goto, K., Masia, R., Sojoodi, M., Arora, G., Aikata, H., Ono, A., Tabrizian, P., Schwartz, M., ... Baumert, T. F. (Accepted/In press). Targeting clinical epigenetic reprogramming for chemoprevention of metabolic and viral hepatocellular carcinoma. Gut, [318918]. https://doi.org/10.1136/gutjnl-2019-318918