@article{864b75e599654cb1a68024653d5b7a2c,
title = "Targeting clinical epigenetic reprogramming for chemoprevention of metabolic and viral hepatocellular carcinoma",
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.",
keywords = "chemoprevention, gene expression, hepatitis C, hepatocellular carcinoma, non-alcoholic steatohepatitis",
author = "Frank J{\"u}hling and Nourdine Hamdane and Emilie Crouchet and Shen Li and {El Saghire}, Houssein and Atish Mukherji and Naoto Fujiwara and Oudot, {Marine A.} and Christine Thumann and Antonio Saviano and {Roca Suarez}, {Armando Andres} and Kaku Goto and Ricard Masia and Mozhdeh Sojoodi and Gunisha Arora and Hiroshi Aikata and Atsushi Ono and Parissa Tabrizian and Myron Schwartz and Polyak, {Stephen J.} and Irwin Davidson and Christian Schmidl and Christoph Bock and Catherine Schuster and Kazuaki Chayama and Patrick Pessaux and Tanabe, {Kenneth K.} and Yujin Hoshida and Zeisel, {Mirjam B.} and Duong, {Fran{\c c}ois H.T.} and Fuchs, {Bryan C.} and Baumert, {Thomas F.}",
note = "Funding Information: Funding This work was supported by the European Union (ERC-AdG2014 HEPCIR #671231 (TFB and YH) and H2020 HEPCAR #667273, ERC PoC-HEPCAN #862551 to TFB). ARC, Paris and Institut Hospitalo-Universitaire, Strasbourg (TheraHCC and TheraHCC2.0 IHUARC IHU201301187 and IHUC201901299 TFB), the Foundation of the University of Strasbourg and Roche Institute (HEPKIN), the Agence Nationale de Recherches sur le Sida et les H{\'e}patites Virales (2017/1633), the US Department of Defense (W81XWH-16-1-0363 to TFB and YH), the Canc{\'e}rop{\^o}le du Grand-Est, the National Institutes of Health (DK099558 and T32CA073145-20 to SL, R01CA233794 to YH and TFB, NCI 1R21CA209940-01A1 to TFB), AMED (19fk0210020h0003 to KC), AASLD Foundation (Pinnacle Research Award) and the Massachusetts General Hospital Department of Surgery (KKT) and the Cancer Prevention & Research Institute of Texas RR180016 to YH. This work has been published under the framework of the LABEX ANR-10-LABX-0028_HEPSYS and PLAN CANCER 2014-2019 HCCMICTAR and benefits from a funding from the state managed by the French National Research Agency as part of the Investments for the Future Program, INCa (National Institute for Cancer) and INSERM. Publisher Copyright: {\textcopyright} ",
year = "2021",
month = jan,
day = "1",
doi = "10.1136/gutjnl-2019-318918",
language = "English (US)",
volume = "70",
pages = "157--169",
journal = "Gut",
issn = "0017-5749",
publisher = "BMJ Publishing Group",
number = "1",
}