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.