本田　浩章
   Department   Research Institutes and Facilities, Research Institutes and Facilities
   Position   Professor
Article types Original article
Language English
Peer review Peer reviewed
Title Dual Regulation of Histone Methylation by mTOR Complexes Controls Glioblastoma Tumor Cell Growth via EZH2 and SAM.
Journal Formal name：Mol Cancer Res
ISSN code：15417786/15573125
Domestic / ForeginForegin
Publisher Philadelphia, PA : American Association for Cancer Research, c2002-
Volume, Issue, Page 18(8),pp.1142-1152
Author and coauthor HARACHI Mio†, MASUI Kenta*, HONDA Hiroaki, MURAGAKI Yoshihiro, KAWAMATA Takakazu, CAVENEE Webster K., MISCHEL Paul S., SHIBATA Noriyuki
Publication date 2020/08
Summary 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.
DOI 10.1158/1541-7786.MCR-20-0024
PMID 32366675