Metabolic Rewiring and the Characterization of Oncometabolites

SIMPLE SUMMARY: Oncometabolites are produced by cancer cells and assist the cancer to proliferate and progress. Oncometabolites occur as a result of mutated enzymes in the tumor tissue or due to hypoxia. These processes result in either the abnormal buildup of a normal metabolite or the accumulation of an unusual metabolite. Definition of the metabolic changes that occur due to these processes has been accomplished using metabolomics, which mainly uses mass spectrometry platforms to define the content of small metabolites that occur in cells, tissues, organs and organisms. The four classical oncometabolites are fumarate, succinate, (2R)-hydroxyglutarate and (2S)-hydroxyglutarate, which operate by inhibiting 2-oxoglutarate-dependent enzyme reactions that principally regulate gene expression and response to hypoxia. Metabolomics has also revealed several putative oncometabolites that include lactate, kynurenine, methylglyoxal, sarcosine, glycine, hypotaurine and (2R,3S)-dihydroxybutanoate. Metabolomics will continue to be critical for understanding the metabolic rewiring involving oncometabolite production that underpins many cancer phenotypes. 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 hypoxia-driven 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-oxoglutarate-dependent 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.