Dual targeting of EZH1 and EZH2 for the treatment of malignant rhabdoid tumors
Malignant rhabdoid tumors (MRTs) are rare and highly aggressive pediatric cancers with no standard of care. MRTs are characterized by loss of SMARCB1, which results in upregulated expression of enhancer of zeste homolog 2 (EZH2), which is responsible for the methylation of lysine 27 of histone H3 (H...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-12-01
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| Series: | Molecular Therapy: Oncolytics |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2372770522001188 |
| _version_ | 1811206356090224640 |
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| author | Haruka Shinohara Rie Sawado Makoto Nakagawa Ayuna Hattori Kazutsune Yamagata Kimiharu Tauchi Jumpei Ito Yasumichi Kuwahara Tsukasa Okuda Chitose Ogawa Issay Kitabayashi |
| author_facet | Haruka Shinohara Rie Sawado Makoto Nakagawa Ayuna Hattori Kazutsune Yamagata Kimiharu Tauchi Jumpei Ito Yasumichi Kuwahara Tsukasa Okuda Chitose Ogawa Issay Kitabayashi |
| author_sort | Haruka Shinohara |
| collection | DOAJ |
| description | Malignant rhabdoid tumors (MRTs) are rare and highly aggressive pediatric cancers with no standard of care. MRTs are characterized by loss of SMARCB1, which results in upregulated expression of enhancer of zeste homolog 2 (EZH2), which is responsible for the methylation of lysine 27 of histone H3 (H3K27me3), leading to the repression of gene expression. Although previous reports suggest EZH2 as an effective therapeutic target, the functions of EZH1, the other homolog of EZH, in MRT remain unknown. Here, we show that EZH1, as well as EZH2, contributes to MRT cell growth and H3K27 methylation. Depletion or selective inhibition of EZH2 led to a compensatory increase in EZH1 expression, and depletion of EZH1 enhanced the effect of EZH2 inhibition. EZH1/2 dual inhibitors suppressed MRT cell growth markedly, reflecting the reduction of H3K27me3 accumulation at one of the EZH1/2 targets, the CDKN2A locus. Dual inhibition of EZH1/2 in vivo suppressed tumor growth completely, with no significant adverse effects. These findings indicate that both EZH1 and EZH2 are potential targets for MRT therapy, and that EZH1/2 dual inhibitors may be promising therapeutic strategies for MRT. |
| first_indexed | 2024-04-12T03:46:04Z |
| format | Article |
| id | doaj.art-20b4e9bb9f2b401e9e56e32a3e37b927 |
| institution | Directory Open Access Journal |
| issn | 2372-7705 |
| language | English |
| last_indexed | 2024-04-12T03:46:04Z |
| publishDate | 2022-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Oncolytics |
| spelling | doaj.art-20b4e9bb9f2b401e9e56e32a3e37b9272022-12-22T03:49:08ZengElsevierMolecular Therapy: Oncolytics2372-77052022-12-01271425Dual targeting of EZH1 and EZH2 for the treatment of malignant rhabdoid tumorsHaruka Shinohara0Rie Sawado1Makoto Nakagawa2Ayuna Hattori3Kazutsune Yamagata4Kimiharu Tauchi5Jumpei Ito6Yasumichi Kuwahara7Tsukasa Okuda8Chitose Ogawa9Issay Kitabayashi10Division of Hematological Malignancy, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-Ku, Tokyo 104-0045, JapanDivision of Hematological Malignancy, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-Ku, Tokyo 104-0045, JapanDivision of Hematological Malignancy, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-Ku, Tokyo 104-0045, Japan; Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, JapanDivision of Hematological Malignancy, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-Ku, Tokyo 104-0045, Japan; Department of Biosystems Science, Institute for Frontier Life and Medical Sciences, Kyoto University, 53 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, JapanDivision of Hematological Malignancy, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-Ku, Tokyo 104-0045, JapanDivision of Hematological Malignancy, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-Ku, Tokyo 104-0045, JapanDivision of Hematological Malignancy, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-Ku, Tokyo 104-0045, Japan; Department of Pediatrics, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, 160-8582 Tokyo, JapanDepartment of Biochemistry and Molecular Biology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, JapanDepartment of Biochemistry and Molecular Biology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, JapanDepartment of Pediatric Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-Ku, Tokyo 104-0045, JapanDivision of Hematological Malignancy, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-Ku, Tokyo 104-0045, Japan; Corresponding author Issay Kitabayashi, Division of Hematological Malignancy, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-Ku, Tokyo 104-0045, Japan.Malignant rhabdoid tumors (MRTs) are rare and highly aggressive pediatric cancers with no standard of care. MRTs are characterized by loss of SMARCB1, which results in upregulated expression of enhancer of zeste homolog 2 (EZH2), which is responsible for the methylation of lysine 27 of histone H3 (H3K27me3), leading to the repression of gene expression. Although previous reports suggest EZH2 as an effective therapeutic target, the functions of EZH1, the other homolog of EZH, in MRT remain unknown. Here, we show that EZH1, as well as EZH2, contributes to MRT cell growth and H3K27 methylation. Depletion or selective inhibition of EZH2 led to a compensatory increase in EZH1 expression, and depletion of EZH1 enhanced the effect of EZH2 inhibition. EZH1/2 dual inhibitors suppressed MRT cell growth markedly, reflecting the reduction of H3K27me3 accumulation at one of the EZH1/2 targets, the CDKN2A locus. Dual inhibition of EZH1/2 in vivo suppressed tumor growth completely, with no significant adverse effects. These findings indicate that both EZH1 and EZH2 are potential targets for MRT therapy, and that EZH1/2 dual inhibitors may be promising therapeutic strategies for MRT.http://www.sciencedirect.com/science/article/pii/S2372770522001188EZH1EZH2H3K27me3malignant rhabdoid tumors (MRTs)epigenetic drugrare cancers |
| spellingShingle | Haruka Shinohara Rie Sawado Makoto Nakagawa Ayuna Hattori Kazutsune Yamagata Kimiharu Tauchi Jumpei Ito Yasumichi Kuwahara Tsukasa Okuda Chitose Ogawa Issay Kitabayashi Dual targeting of EZH1 and EZH2 for the treatment of malignant rhabdoid tumors Molecular Therapy: Oncolytics EZH1 EZH2 H3K27me3 malignant rhabdoid tumors (MRTs) epigenetic drug rare cancers |
| title | Dual targeting of EZH1 and EZH2 for the treatment of malignant rhabdoid tumors |
| title_full | Dual targeting of EZH1 and EZH2 for the treatment of malignant rhabdoid tumors |
| title_fullStr | Dual targeting of EZH1 and EZH2 for the treatment of malignant rhabdoid tumors |
| title_full_unstemmed | Dual targeting of EZH1 and EZH2 for the treatment of malignant rhabdoid tumors |
| title_short | Dual targeting of EZH1 and EZH2 for the treatment of malignant rhabdoid tumors |
| title_sort | dual targeting of ezh1 and ezh2 for the treatment of malignant rhabdoid tumors |
| topic | EZH1 EZH2 H3K27me3 malignant rhabdoid tumors (MRTs) epigenetic drug rare cancers |
| url | http://www.sciencedirect.com/science/article/pii/S2372770522001188 |
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