Hypoxia-Induced Epigenetic Dysregulation Promotes Infantile Ependymoma

Posterior fossa A (PFA) ependymomas are the second most common hindbrain malignancies found in infants and toddlers, arising from a cell lineage present only during the first trimester. PFA ependymomas lack recurrent somatic mutations but have epigenetic dysregulation, and they develop in a low-oxygen environment and exhibit elevated hypoxic signaling, leading Michealraj, Kumar, Kim, and colleagues to investigate the link between hypoxia and the epigenome in this cancer. In vitro experiments using patient-derived PFA ependymoma cells showed that these cells strictly depended on hypoxic conditions for survival. Metabolic regulation was different in PFA ependymoma cells compared with other ependymomas or normal brain tissue—for example, glycolysis, nonoxidative pentose phosphate and polyamine metabolism were enriched in PFA ependymomas. PFA ependymomas also exhibited altered histone 3 lysine residue 27 methylation and acetylation (H3K27me and H3K27ac, respectively), with global reductions in H3K27me2 and H3K27me3 and increased H3K27ac. In vitro experiments showed that hypoxia was required to maintain this histone-modification profile and demonstrated that PFA ependymomas required high glucose levels, especially when exposed to higher oxygen levels. Mechanistically, hypoxia increased expression of genes encoding PRC2 inhibitors and reduced levels of S-adenosyl-L-methionine, a substrate for the histone methyltransferase and PRC2 component EZH2, maintaining low H3K27me3 levels. Further contributing to global hypomethylation, hypoxia-induced glutaminolysis elevated the production of α-ketoglutarate, increasing the activity of the H3K27 demethylases KDM6A/B. Concurrently, hypoxia-driven glutaminolysis followed by reductive carboxylation generated acetyl-Coenzyme A, increasing H3K27ac (and thus blocking EZH2-mediated methylation). Seemingly paradoxically, a CRISPR–Cas9-based knockout screen revealed that the genes encoding EZH2 and two other core components of PRC2 (EED and SUZ12) were most essential in PFA ependymomas, and deeper investigation supported a “Goldilocks” model in which PFA ependymomas are especially sensitive to perturbations to their low H3K27 methylation and high H3K27 acetylation levels. An analysis of normal murine fetal hindbrain cells showed that the characteristic metabolic phenotype observed in PFA ependymomas was similar to that of cells of the gliogenic lineage in the developing hindbrain. In summary, this work elucidates the molecular connection between hypoxic metabolism and epigenetic dysregulation in PFA ependymoma.

Michealraj KA, Kumar SA, Kim LJY, Cavalli FMG, Przelicki D, Wojcik JB, et al. Metabolic regulation of the epigenome drives lethal infantile ependymoma. Cell 2020;181:1329–45.e24.

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