Cancer Cell: Multi-group analysis helps search for metabolic "breaks" of malignant gliomas

Diffuse congenital brain bridge glioma (DIPG) is a highly invasive brain stem tumor in children, in which more than 80% of patients have histone H3K27-bit clutter point mutation (H3K27M), which causes a decrease in the overall H3K27me3 level.
because DIPG cannot be surgically removed and conventional chemotherapy has little effect on it, there is an urgent need to find an effective DIPG treatment.
currently, one of the main therapeutic ideas for carrying the H3K27M mutation DIPG is to increase the level of H3K27me3 in cells by an osctic way to inhibit tumor growth.
August 13, 2020, professor Sriram Venneti of the University of Michigan published an article entitled Integrated Metabolic and Epigenomic Reprograming by H3K27M Mutations in Diffuse Intrinsic Pontine Gliomas on Canser Cell, USA. The diffuse congenital brain bridge glioma (DIPG), which carries the H3K27M mutation, is reported to maintain intracellular ɑ-KG at a high level through metabolic reprogramming, which in turn activates the dioxygenase with ɑ-KG as a secondary factor, reducing the level of H3K27me3 in cells.
based on this metabolic characteristic, the authors propose a new strategy for killing H3K27M DIPG by targeting the generation of ɑ-KG.
First, to explore the metabolic characteristics of H3K27M DIPG, the authors integrated transcription, proteomics, and metabolic groups to conduct multi-histological analysis of H3.3WT and H3K27M mutant mouse neuron stem cells (NSCs), and found that the levels of NSCs with H3K27M mutations increased with TCA circulation.
, the authors again came to this conclusion by conducting single-cell sc RNA-seq and magnetic resonance spectral analysis (MRS) of tumor samples from DIPG patients.
, the results of metabolomics show that alpha-KG levels in cells with H3K27M mutations increase significantly compared to WT cells, while alpha-KG, as a cofactor of a series of demethylases (e.g., TET, KDMs), has an important regulatory effect on methylation levels of endocrine in cells.
, the authors speculate that elevated alpha-KG in H3K27M cells may be a significant cause of the decline in H3K27me3 levels in cells.
, the authors tested this hypothesis at the cellular level.
authors found that Glutamine and Glass hunger treatment of cells carrying the H3K27M mutation significantly increased H3K27me3 levels and significantly inhibited cell proliferation, while WT had a relatively small cell impact, and that this ideotype recovered after esterified alpha-KG was added to the cells.
further, the same experimental phenomena were observed by inhibiting Glutamine and Glacose to produce metabolic enzymes in alpha-KG path pathps such as GDH, HK2, IDH1/2.
results show that blocking alpha-KG produced by Glutamine and Glacose can increase H3K27me3 levels of mutant cells containing H3K27M, thereby inhibiting the growth of DIPG, which carries the mutation.
, considering that this metabolic characteristic of H3K27M mutation DIPG has a very important clinical application prospect, the authors further verified the animal level.
the authors selected two small molecular inhibitors that could cross the blood-brain barrier, JHU-083 (glutamine structural similarity) and a co-priced binding inhibitor for IDH.
the authors found that both inhibitors were effective in inhibiting the growth of H3K27M DIPG in mice, and that the combined effect was more significant.
, the team used multi-histological studies to identify an important metabolic feature of DIPG carrying the H3K27M mutation, which relies on glycolysis and TCA cycles to maintain high alpha-KG pools, which in turn put the H3K27 bits at low methylation levels.
, the findings provide a new therapeutic target for this type of DIPG.
It's worth noting that previous studies have reported that gliomas carrying IDH1/2 mutations produce a large number of alpha-KG structural similarities, D-2HG, which in turn competitively inhibits the increased activity of methylase in cells. The seemingly contradictory phenomenon of methylation levels of histones suggests that the two glioma cells take the opposite approach to regulating alpha-KG levels and thus maintaining their most appropriate oscillosurities, so these two mutations are highly specialized for glioma cells.
same time, the authors' findings suggest that man-made combinations of these two mutations can have a "synthetic lethal" effect on cells, a finding that may provide new ideas for the treatment of both gliomas.
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