Integrative Epigenetic Analysis Reveals Therapeutic Targets to the DNA Methyltransferase Inhibitor Guadecitabine (SGI-110) in Hepatocellular Carcinoma

Hepatology : Official Journal of the American Association for the Study of Liver Diseases
Minmin LiuGangning Liang

Abstract

There is an urgent need to develop more effective therapies for hepatocellular carcinoma (HCC) because of its aggressiveness. Guadecitabine (SGI-110) is a second-generation DNA methyltransferase inhibitor (DNMTi), which is currently in clinical trials for HCC and shows greater stability and performance over first-generation DNMTis. In order to identify potential therapeutic targets of SGI-110 for clinical trials, HCC cell lines (SNU398, HepG2, and SNU475) were used to evaluate the effects of transient SGI-110 treatment by an integrative analysis of DNA methylation, nucleosome accessibility, gene expression profiles, and its clinical relevance by comparison to The Cancer Genome Atlas (TCGA) HCC clinical data. Each HCC cell line represents a different DNA methylation subtype of primary HCC tumors based on TCGA data. After SGI-110 treatment, all cell lines were sensitive to SGI-110 with prolonged antiproliferation effects. Expression of up-regulated genes, including tumor suppressors, was positively correlated with nucleosome accessibility and negatively correlated with gene promoter DNA methylation. Alternatively, expression of down-regulated genes, such as oncogenes, was negatively correlated with nucleosome accessibility and po...Continue Reading

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Citations

Aug 3, 2018·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Ryan A Hlady, Keith D Robertson
Apr 18, 2019·Expert Review of Gastroenterology & Hepatology·Tobias Kiesslich, Daniel Neureiter
Feb 6, 2020·International Journal of Cancer. Journal International Du Cancer·Tong XuAmir Goldkorn
Jan 5, 2020·Nature Reviews. Gastroenterology & Hepatology·Bin ChenXin Chen
Jan 6, 2021·Journal of Cell Communication and Signaling·Andrés Hernández-OliverasJuan Santiago-García
Apr 4, 2021·Cancers·María ArechederraCarmen Berasain
Jul 30, 2021·Seminars in Cancer Biology·Ganji Purnachandra NagarajuBassel F El-Rayes
Aug 28, 2021·Cancers·Ewa Wolinska, Maciej Skrzypczak

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