Evaluation of epigenetic resistance mechanisms of a multikinase inhibitor in hepatocellular carcinoma

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K17482
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Chiba University
• Principal Investigator: Kusakabe Yuko 千葉大学, 大学院医学研究院, 特任助教 (30646708)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: エピジェネティクス / 肝細胞癌 / ヒストン修飾

Outline of Final Research Achievements

It has been reported that EZH1/2 inhibits the transcription of target genes via H3 lysine 27 trimethylation (H3K27me3) and is involved in carcinogenesis. According to a study that used surgical specimens from patients with hepatocellular carcinoma (HCC), a high H3K27me3 level is associated with a poor prognosis and EZH1/2 inhibition significantly suppresses cell proliferation of liver cancer cells. Sorafenib, an existing agent used to treat liver cancer, inhibits EZH2 phosphorylation at serine 21 via Akt, resulting in an increase in the H3K27me3 level. A combination use of sorafenib and EZH1/2 inhibitors exhibits potent antitumor activity.

Free Research Field

消化器内科学

Academic Significance and Societal Importance of the Research Achievements

肝細胞癌においてEZH2のみならずEZH1もH3K27me3レベルの上昇を介して癌の進行に重要な役割を担うことが示唆された。またマルチキナーゼ阻害剤であるソラフェニブがH3K27me3レベルを上昇させることで薬剤の耐性に関与する可能性があり、EZH1/2阻害剤とソラフェニブの併用は肝細胞癌の新たな治療戦略となる可能性が示された。