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

Author:

Jühling Frank,Hamdane Nourdine,Crouchet Emilie,Li Shen,El Saghire Houssein,Mukherji Atish,Fujiwara NaotoORCID,Oudot Marine A,Thumann Christine,Saviano Antonio,Roca Suarez Armando Andres,Goto Kaku,Masia Ricard,Sojoodi MozhdehORCID,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 BORCID,Duong François HT,Fuchs Bryan C,Baumert Thomas FORCID

Abstract

ObjectiveHepatocellular 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.DesignLiver 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.ResultsIn 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.ConclusionOur 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.

Publisher

BMJ

Subject

Gastroenterology

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