Concept: Oncometabolites. Also: Dynamic interplay of metabolome and epigenome.
Source: News and Views in Nature (April 3, 2013) of a study published in Science.
- Background: It was already known that mutations in proteins involved in metabolism may be associated with cancer, but this is the first study to show that a metabolite may be sufficient for oncogenesis. Previous studies identified mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) in (75% of) brain tumours and (20% of) leukemia. IDH1/2 act in the citric acid cycle to convert isocitrate to alpha-ketoglutarate. The mutation confers on IDH1/2 the ability to convert alpha-ketoglutarate to (R)-2HG.
- Result: Addition of (R)-2HG is sufficient to transform cells. It does this by: (1) inhibiting TET2 (which acts to methylate histones) resulting in histone hypermethylation resulting in blockage of cell differentiation; and (2) synergizing the activity of the alpha-ketoglutarate target EGLN, which acts to inhibit (by marking for degradation) HIF-alpha, which is a transcription factor that inhibits proliferation and promotes differentiation.
- An implication: This adds detail to the dynamic interplay of the metabolic and epigenetic landscapes.
