Cancer-Causing Mutations Disrupt Cells’ Ability to Differentiate

Researchers have published a series of three papers today in the journal Nature, explaining some of the mysteries of how the mutations in a gene called isocitrate dehydrogenase 1 (IDH1) cause brain cancer and leukemia. The mutations cause the production of an enzyme that can reconfigure on-off switches across the genome and stop cells from differentiating.

The findings could be used to develop drugs to treat these mutations, something that pharmaceutical companies have already started.

IDH1 is an energy-generating pathway, known as the citric-acid cycle, and the mutations associated with cancer cause the metabolite 2-hydroxyglutarate to accumulate. The mutations have been identified through several genome projects as part of an interest in understanding the unusual metabolism of cancer cells.

IDH1 mutations can be found in multiple cancers and researchers had been struggling to find out how the changes contribute to cancer. Now, scientists have identified several ways in which IDH1 mutations contribute to the disease. The form of 2-hydroxyglutarate that accumulates in IDH1-mutant cancer cells promotes cell growth by inhibiting the activity of the protein hypoxia inducible factor (HIF), which in turn can sometimes suppress tumors.

The IDH1 mutations unleash epigenetic chaos, by interfering with an enzyme that regulates the deposition of methyl groups on DNA, which can switch gene expression on and off. Researchers also showed that changing the methylation state of histones, crucial DNA-protein complexes, prevents the cells from differentiating, which bears the hallmark of cancer cells.

Reference: “Cancer-causing mutations yield their secrets” by Heidi Ledford, 15 February 2012, Nature.
DOI: 10.1038/nature.2012.10029

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