Juhling, Frank and Hamdane, Nourdine and Crouchet, Emilie and Li, Shen and El Saghire, Houssein and Mukherji, Atish and Fujiwara, Naoto and Oudot, Marine A. and Thumann, Christine and Saviano, Antonio and Suarez, Armando Andres Roca and Goto, Kaku and Masia, Ricard and Sojoodi, Mozhdeh and Arora, Gunisha and Aikata, Hiroshi and Ono, Atsushi and Tabrizian, Parissa and Schwartz, Myron and Polyak, Stephen J. and Davidson, Irwin and Schmidl, Christian and Bock, Christoph and Schuster, Catherine and Chayama, Kazuaki and Pessaux, Patrick and Tanabe, Kenneth K. and Hoshida, Yujin and Zeisel, Mirjam B. and Duong, Francois H. T. and Fuchs, Bryan C. and Baumert, Thomas F. (2021) Targeting clinical epigenetic reprogramming for chemoprevention of metabolic and viral hepatocellular carcinoma. GUT, 70 (1). pp. 157-169. ISSN 0017-5749, 1468-3288
Full text not available from this repository. (Request a copy)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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | MUTATIONAL LANDSCAPE; CANCER; INHIBITION; PREVENTION; CIRRHOSIS; PATHWAY; RISK; HCV; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Zentren des Universitätsklinikums Regensburg > Regensburger Centrum für Interventionelle Immunologie (RCI) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 27 Sep 2022 09:22 |
| Last Modified: | 27 Sep 2022 09:22 |
| URI: | https://pred.uni-regensburg.de/id/eprint/48048 |
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