Dual Regulation of Histone Methylation by mTOR Complexes Controls Glioblastoma Tumor Cell Growth via EZH2 and SAM
| Autor: | Yoshihiro Muragaki, Webster K. Cavenee, Takakazu Kawamata, Noriyuki Shibata, Hiroaki Honda, Paul S. Mischel, Kenta Masui, Mio Harachi |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research S-Adenosylmethionine Mechanistic Target of Rapamycin Complex 2 Biology Mechanistic Target of Rapamycin Complex 1 mTORC2 Epigenesis Genetic Histones 03 medical and health sciences Histone H3 Mice 0302 clinical medicine Cell Line Tumor Histone methylation Animals Humans Enhancer of Zeste Homolog 2 Protein Epigenetics Molecular Biology Cell Proliferation EZH2 DNA Methylation Up-Regulation Gene Expression Regulation Neoplastic 030104 developmental biology Histone Oncology Tumor progression 030220 oncology & carcinogenesis DNA methylation biology.protein Cancer research Glioblastoma Neoplasm Transplantation |
| Zdroj: | Molecular cancer research : MCR. 18(8) |
| ISSN: | 1557-3125 |
| Popis: | Epigenetic regulation known for DNA methylation and histone modification is critical for securing proper gene expression and chromosomal function, and its aberration induces various pathologic conditions including cancer. Trimethylation of histone H3 on lysine 27 (H3K27me3) is known to suppress various genes related to cancer cell survival and the level of H3K27me3 may have an influence on tumor progression and malignancy. However, it remains unclear how histone methylation is regulated in response to genetic mutation and microenvironmental cues to facilitate the cancer cell survival. Here, we report a novel mechanism of the specific regulation of H3K27me3 by cooperatively two mTOR complexes, mTORC1 and mTORC2 in human glioblastoma (GBM). Integrated analyses revealed that mTORC1 upregulates the protein expression of enhancer of zeste homolog 2, a main component of polycomb repressive complex 2 which is known as H3K27-specific methyltransferase. The other mTOR complex, mTORC2, regulates production of S-adenosylmethionine, an essential substrate for histone methylation. This cooperative regulation causes H3K27 hypermethylation which subsequently promotes tumor cell survival both in vitro and in vivo xenografted mouse tumor model. These results indicate that activated mTORC1 and mTORC2 complexes cooperatively contribute to tumor progression through specific epigenetic regulation, nominating them as an exploitable therapeutic target against cancer. Implications: A dynamic regulation of histone methylation by mTOR complexes promotes tumor growth in human GBM, but at the same time could be exploitable as a novel therapeutic target against this deadly tumor. |
| Databáze: | OpenAIRE |
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