ムラガキ ヨシヒロ   MURAGAKI Yoshihiro
  村垣 善浩
   所属   研究施設 研究施設
   職種   教授
論文種別 原著
言語種別 英語
査読の有無 査読あり
表題 Dual Regulation of Histone Methylation by mTOR Complexes Controls Glioblastoma Tumor Cell Growth via EZH2 and SAM.
掲載誌名 正式名:Molecular cancer research : MCR
略  称:Mol Cancer Res
ISSNコード:15417786/15573125
掲載区分国外
出版社 Philadelphia, PA : American Association for Cancer Research, c2002-
巻・号・頁 Epub ahead of print頁
著者・共著者 HARACHI Mio†, MASUI Kenta, HONDA Hiroaki, MURAGAKI Yoshihiro, KAWAMATA Takakazu, CAVENEE Webster K., MISCHEL Paul S., SHIBATA Noriyuki
発行年月 2020/05/04
概要 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