Editors' ChoiceGlioblastoma

H3 Minority Report

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Science Translational Medicine  17 Apr 2013:
Vol. 5, Issue 181, pp. 181ec66
DOI: 10.1126/scitranslmed.3006317

Cancers of glial cells, known as gliomas, make up ~30% of all tumors of the brain and spinal cord. Pediatric gliomas, such as glioblastoma mutiforme (GBM) and diffuse intrinsic pontine gliomas (DIPG), are devastating brain tumors without effective therapies that most frequently occur in children. Recent advances in tumor sequencing have revealed an abundance of a particular somatic mutation in ~60% of pediatric GBMs and DIPGs in a protein involved in packaging DNA: histone H3. Now, Lewis et al. reveal that the H3-specific substitution of the amino acid lysine (K) for methionine (M) at position 27 (H3K27) results in a “poisonous” gain-of-function that causes global inhibition of H3K27 methylation in these tumors. In this newly discovered pathway, minor amounts of mutated histones become the cause of enzymatic impairment followed by global defects in histone methylation that may underlie disease pathology.

Histones, which comprise the bulk of nuclear proteins, are required for packaging of the DNA into chromatin and for regulation of gene function. Posttranslational H3K27 methylation could be justly considered as a holy grail of gene regulation; it controls cell differentiation, cell division, and X-chromosome inactivation. The specific K to M substitution identified in brain tumors by the authors affects only a small fraction of total H3K27 residues. However, this relatively minor imperfection, as compared with the overall bulk of histone, turns out to be a powerful poison for global H3K27 methylation. Using an in vitro cell culture system, Lewis et al. showed that the presence of small amounts (~1%) of the mutant H3 extracted from human cancer cells was sufficient to nearly ablate endogenous H3K27me2/3 levels. This global effect on H3K27me was caused by the ability of the mutant histone to reduce the catalytic activity of the enzyme Ezh2, which is solely responsible for H3K27me2/3. Although this reduction in PRC2-dependent histone methyltransferase activity was restricted to the H3K27M mutation (none of the other K27X mutations tested caused a decrease in endogenous H3K27 methylation), Lewis et al. revealed a surprising conservation; the histone methyltransferase K to M mutation caused a similar inhibition at two additional, functionally important H3 lysine methylation sites. Although the H3K9M or H3K36M mutations have not yet been linked to human diseases, the conservation of the toxic gain-of-function mechanism exposes a chilling vulnerability of histone-dependent gene expression regulation.

The detailed stoichiometry for the described events remains elusive because it is not clear how a H3 minority gains access to most of the cellular Ezh2. It cannot be entirely excluded that the “intoxicated” Ezh2 acquires novel properties that can amplify the inactivation reaction. With many questions to be answered, this newly discovered epigenetic paradigm reveals a potent regulatory circuitry in which histone gene mutation or histone RNA editing may provide powerful mechanisms for the regulation of gene expression in health and disease.

P. W. Lewis et al., Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma. Science, published online 28 March 2013 (10.1126/science.1232245). [Abstract]

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