Targeting clinical epigenetic reprogramming for chemoprevention of metabolic and viral hepatocellular carcinoma.
chemoprevention
gene expression
hepatitis C
hepatocellular carcinoma
non-alcoholic steatohepatitis
Journal
Gut
ISSN: 1468-3288
Titre abrégé: Gut
Pays: England
ID NLM: 2985108R
Informations de publication
Date de publication:
01 2021
01 2021
Historique:
received:
17
04
2019
revised:
05
03
2020
accepted:
05
03
2020
pubmed:
29
3
2020
medline:
31
7
2021
entrez:
29
3
2020
Statut:
ppublish
Résumé
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. 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 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. 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.
Identifiants
pubmed: 32217639
pii: gutjnl-2019-318918
doi: 10.1136/gutjnl-2019-318918
pmc: PMC7116473
mid: EMS96042
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
157-169Subventions
Organisme : European Research Council
ID : 755460
Pays : International
Organisme : European Research Council
ID : 862551
Pays : International
Organisme : NCI NIH HHS
ID : R21 CA209940
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK099558
Pays : United States
Organisme : European Research Council
ID : 671231
Pays : International
Organisme : NCI NIH HHS
ID : R01 CA233794
Pays : United States
Informations de copyright
© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
Déclaration de conflit d'intérêts
Competing interests: The University of Strasbourg, INSERM, the IHU Strasbourg and Mount Sinai Hospital have filed a patent application on the clinical gene signature-based human cell culture model and uses thereof with YH and TFB as co-inventors (WO 2016174130 A1), which has been licensed to Alentis Therapeutics, Basel, Switzerland.
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