EZH1/2 inhibition augments the anti-tumor effects of sorafenib in hepatocellular carcinoma

Yuko Kusakabe, Tetsuhiro Chiba, Motohiko Oshima, Shuhei Koide, Ola Rizq, Kazumasa Aoyama, Junjie Ao, Tatsuya Kaneko, Hiroaki Kanzaki, Kengo Kanayama, Takahiro Maeda, Tomoko Saito, Ryo Nakagawa, Kazufumi Kobayashi, Soichiro Kiyono, Masato Nakamura, Sadahisa Ogasawara, Eiichiro Suzuki, Shingo Nakamoto, Shin YasuiRintaro Mikata, Ryosuke Muroyama, Tatsuo Kanda, Hitoshi Maruyama, Jun Kato, Naoya Mimura, Anqi Ma, Jian Jin, Yoh Zen, Masayuki Otsuka, Atsushi Kaneda, Atsushi Iwama, Naoya Kato

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Both EZH2 and its homolog EZH1 function as histone H3 Lysine 27 (H3K27) methyltransferases and repress the transcription of target genes. Dysregulation of H3K27 trimethylation (H3K27me3) plays an important role in the development and progression of cancers such as hepatocellular carcinoma (HCC). This study investigated the relationship between the expression of EZH1/2 and the level of H3K27me3 in HCC. Additionally, the role of EZH1/2 in cell growth, tumorigenicity, and resistance to sorafenib were also analyzed. Both the lentiviral knockdown and the pharmacological inhibition of EZH1/2 (UNC1999) diminished the level of H3K27me3 and suppressed cell growth in liver cancer cells, compared with EZH1 or EZH2 single knockdown. Although a significant association was observed between EZH2 expression and H3K27me3 levels in HCC samples, overexpression of EZH1 appeared to contribute to enhanced H3K27me3 levels in some EZH2lowH3K27me3high cases. Akt suppression following sorafenib treatment resulted in an increase of the H3K27me3 levels through a decrease in EZH2 phosphorylation at serine 21. The combined use of sorafenib and UNC1999 exhibited synergistic antitumor effects in vitro and in vivo. Combination treatment canceled the sorafenib-induced enhancement in H3K27me3 levels, indicating that activation of EZH2 function is one of the mechanisms of sorafenib-resistance in HCC. In conclusion, sorafenib plus EZH1/2 inhibitors may comprise a novel therapeutic approach in HCC.

Original languageEnglish
Article number21396
JournalScientific Reports
Volume11
Issue number1
DOIs
StatePublished - Dec 2021

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