Intriguing study: icocitrate dehydrogenase-1 serves to derepress an oncogene (!!)

In the late 2000’s it was discovered that mutations in IDH1, the gene encoding the enzyme isocitrate dehydrogenase-1, are often associated with glioma, the most common form of brain cancer. This finding was quite unexpected and tantalizing. The IDH1 pro­tein is involved in the citric-acid cycle — a metabolic process that is used by nearly all cells to generate energy, and in 2008 was the first time it had been connected to any form of cancer.

Gain-of-function IDH mutations are initiating events that define major clinical and prognostic classes of gliomas. The mutant IDH protein produces a new onco-metabolite,

2-hydroxyglutarate, which interferes with iron-dependent hydroxylases, including the TET family of 5-methylcytosine hydroxylases. TET enzymes catalyze a key step in the removal of DNA methylation. IDH mutant gliomas therefore manifest a CpG island methylator phenotype (G-CIMP), although the functional importance of this altered

epigenetic state has remained unclear.

 Authors [ref. below] show that human IDH mutant gliomas exhibit hypermethylation at cohesin and CCCTC-binding factor (CTCF)-binding sites, compromising binding of this methylation-sensitive insulator protein. Decreased CTCF binding is associated with loss of insulation between topological domains and aberrant gene activation. Authors specifically demonstrate that loss of CTCF at a domain boundary permits a constitutive enhancer to interact aberrantly with the receptor tyrosine kinase gene PDGFRA, a prominent glioma oncogene. Treatment of IDH mutant gliomaspheres with a demethylating agent can partially restore insulator function and down-regulates PDGFRA. Conversely, CRISPR-mediated disruption of the CTCF motif in IDH wild-type gliomaspheres up-regulates PDGFRA and increases proliferation.  These intriguing findins suggest that IDH mutations promote gliomagenesis by disrupting chromosomal topology and allowing aberrant regulatory interactions that induce oncogene expression.

 Nature  7 Jan 2o16; 529: 110-114   and editorial, pp 34-35

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