EZH1/2 inhibition augments the anti-tumor effects of sorafenib in hepatocellular carcinoma
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 (...
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Nature Portfolio
2021-11-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-021-00889-0 |
| _version_ | 1818922152630419456 |
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| author | 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 Yasui Rintaro 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 |
| author_facet | 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 Yasui Rintaro 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 |
| author_sort | Yuko Kusakabe |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-20T01:49:00Z |
| format | Article |
| id | doaj.art-8eb58697caf4466e8a01b8253f2d212f |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-20T01:49:00Z |
| publishDate | 2021-11-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj.art-8eb58697caf4466e8a01b8253f2d212f2022-12-21T19:57:41ZengNature PortfolioScientific Reports2045-23222021-11-0111111410.1038/s41598-021-00889-0EZH1/2 inhibition augments the anti-tumor effects of sorafenib in hepatocellular carcinomaYuko Kusakabe0Tetsuhiro Chiba1Motohiko Oshima2Shuhei Koide3Ola Rizq4Kazumasa Aoyama5Junjie Ao6Tatsuya Kaneko7Hiroaki Kanzaki8Kengo Kanayama9Takahiro Maeda10Tomoko Saito11Ryo Nakagawa12Kazufumi Kobayashi13Soichiro Kiyono14Masato Nakamura15Sadahisa Ogasawara16Eiichiro Suzuki17Shingo Nakamoto18Shin Yasui19Rintaro Mikata20Ryosuke Muroyama21Tatsuo Kanda22Hitoshi Maruyama23Jun Kato24Naoya Mimura25Anqi Ma26Jian Jin27Yoh Zen28Masayuki Otsuka29Atsushi Kaneda30Atsushi Iwama31Naoya Kato32Department of Gastroenterology, Graduate School of Medicine, Chiba UniversityDepartment of Gastroenterology, Graduate School of Medicine, Chiba UniversityDivision of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of TokyoDivision of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of TokyoDivision of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of TokyoDepartment of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba UniversityDepartment of Gastroenterology, Graduate School of Medicine, Chiba UniversityDepartment of Gastroenterology, Graduate School of Medicine, Chiba UniversityDepartment of Gastroenterology, Graduate School of Medicine, Chiba UniversityDepartment of Gastroenterology, Graduate School of Medicine, Chiba UniversityDepartment of Gastroenterology, Graduate School of Medicine, Chiba UniversityDepartment of Gastroenterology, Graduate School of Medicine, Chiba UniversityDepartment of Gastroenterology, Graduate School of Medicine, Chiba UniversityDepartment of Gastroenterology, Graduate School of Medicine, Chiba UniversityDepartment of Gastroenterology, Graduate School of Medicine, Chiba UniversityDepartment of Gastroenterology, Graduate School of Medicine, Chiba UniversityDepartment of Gastroenterology, Graduate School of Medicine, Chiba UniversityDepartment of Gastroenterology, Graduate School of Medicine, Chiba UniversityDepartment of Gastroenterology, Graduate School of Medicine, Chiba UniversityDepartment of Gastroenterology, Graduate School of Medicine, Chiba UniversityDepartment of Gastroenterology, Graduate School of Medicine, Chiba UniversityDepartment of Molecular Virology, Graduate School of Medicine, Chiba UniversityDepartment of Gastroenterology and Hepatology, Nihon University School of MedicineDepartment of Gastroenterology, Juntendo University School of MedicineDepartment of Gastroenterology, Graduate School of Medicine, Chiba UniversityDepartment of Transfusion Medicine and Cell Therapy, Chiba UniversityMount Sinai Center for Therapeutics Discovery, Icahn School of Medicine at Mount SinaiMount Sinai Center for Therapeutics Discovery, Icahn School of Medicine at Mount SinaiInstitute of Liver Studies, King’s College HospitalDepartment of General Surgery, Graduate School of Medicine, Chiba UniversityDepartment of Molecular Oncology, Graduate School of Medicine, Chiba UniversityDivision of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of TokyoDepartment of Gastroenterology, Graduate School of Medicine, Chiba UniversityAbstract 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.https://doi.org/10.1038/s41598-021-00889-0 |
| spellingShingle | 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 Yasui Rintaro 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 EZH1/2 inhibition augments the anti-tumor effects of sorafenib in hepatocellular carcinoma Scientific Reports |
| title | EZH1/2 inhibition augments the anti-tumor effects of sorafenib in hepatocellular carcinoma |
| title_full | EZH1/2 inhibition augments the anti-tumor effects of sorafenib in hepatocellular carcinoma |
| title_fullStr | EZH1/2 inhibition augments the anti-tumor effects of sorafenib in hepatocellular carcinoma |
| title_full_unstemmed | EZH1/2 inhibition augments the anti-tumor effects of sorafenib in hepatocellular carcinoma |
| title_short | EZH1/2 inhibition augments the anti-tumor effects of sorafenib in hepatocellular carcinoma |
| title_sort | ezh1 2 inhibition augments the anti tumor effects of sorafenib in hepatocellular carcinoma |
| url | https://doi.org/10.1038/s41598-021-00889-0 |
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