Dual Regulation of Histone Methylation by mTOR Complexes Controls Glioblastoma Tumor Cell Growth via EZH2 and SAM

Abstract

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.

Metabolic Reprogramming Drives Pituitary Tumor Growth through Epigenetic Regulation of TERT

“…Immunostaining was performed as described previously [8,22]. Slides were counterstained with hematoxylin or DAPI (Invitrogen, Waltham, MA) to visualize nuclei.…”

“…Immunoprecipitated chromatin was washed and de-crosslinked, and purified DNA was quantified by TB-Green real-time quantitative PCR. Recoveries were calculated as percent of input according to the previously reported methods [8,22].…”

“…Metabolic reprogramming is an emerging, core hallmark of cancer, which meets an energetic demand of proliferating tumor cells [4,6]. Recently, epigenetic changes including histone modifications through metabolic reprogramming were reported to be involved in neoplastic development, including pituitary tumorigenesis [8,10,20,29,30].…”

A review of dynamical systems approaches for the detection of chaotic attractors in cancer networks

“…For instance, while the H3K27M mutant is a glioma phenotype associated with a lack of methylation, recent studies show mammalian target of rapamycin ( mTOR) complexes promote the hypermethylation of H3K27 (in the form of trimethylated lysine 27 of histone H3 [i.e., H3K27me3]) that influence tumor progression and malignancy. 50 For simplicity, the epigenetic dysregulations, which serve as hallmarks of pediatric brain cancers, will not be discussed here. Rather it is implied that the dynamics of the discussed transcriptional network modules are inseparable from the aberrant changes in their epigenetic networks.…”

Protein Acetylation at the Interface of Genetics, Epigenetics and Environment in Cancer

“…Novel approaches to selectively inhibit mTORC2 are emerging, which potentially provide more specific anti-cancer effects, including the targeting of complex-specific protein-protein interactions [135], and the disruption of mTORC2 substrate recruitment [136]. The demonstration that mTOR-targeting therapies could be effective cancer therapeutics through the modulation of cancer metabolism and epigenetics [137], and the future development of specific and accurate ways to inhibit mTORC2 activity represent promising strategies to target cancer metabolism and protein PTM networks.…”