Metabolic rewiring and the characterization of oncometabolites

Abstract

The study of low-molecular-weight metabolites that exist in cells and organisms is known as metabolomics and is often conducted using mass spectrometry laboratory platforms. Definition of oncometabolites in the context of the metabolic phenotype of cancer cells has been accomplished through metabolomics. Oncometabolites result from mutations in cancer cell genes or from hypoxiadriven enzyme promiscuity. As a result, normal metabolites accumulate in cancer cells to unusually high concentrations or, alternatively, unusual metabolites are produced. The typical oncometabolites fumarate, succinate, (2R)-hydroxyglutarate and (2S)-hydroxyglutarate inhibit 2-oxoglutaratedependent dioxygenases, such as histone demethylases and HIF prolyl-4-hydroxylases, together with DNA cytosine demethylases. As a result of the cancer cell acquiring this new metabolic phenotype, major changes in gene transcription occur and the modification of the epigenetic landscape of the cell promotes proliferation and progression of cancers. Stabilization of HIF1α through inhibition of HIF prolyl-4-hydroxylases by oncometabolites such as fumarate and succinate leads to a pseudohypoxic state that promotes inflammation, angiogenesis and metastasis. Metabolomics has additionally been employed to define the metabolic phenotype of cancer cells and patient biofluids in the search for cancer biomarkers. These efforts have led to the uncovering of the putative oncometabolites sarcosine, glycine, lactate, kynurenine, methylglyoxal, hypotaurine and (2R,3S)-dihydroxybutanoate, for which further research is required.