Oncometabolites: linking altered metabolism with cancer

Abstract

The discovery of cancer-associated mutations in genes encoding key metabolic enzymes has provided a direct link between altered metabolism and cancer. Advances in mass spectrometry and nuclear magnetic resonance technologies have facilitated high-resolution metabolite profiling of cells and tumors and identified the accumulation of metabolites associated with specific gene defects. Here we review the potential roles of such "oncometabolites" in tumor evolution and as clinical biomarkers for the detection of cancers characterized by metabolic dysregulation. IntroductionThe emerging interest in metabolites whose abnormal accumulation causes both metabolic and nonmetabolic dysregulation and potential transformation to malignancy (herein termed "oncometabolites") has been fueled by the identification of cancerassociated mutations in genes encoding enzymes with significant roles in cellular metabolism (1-5). Loss-of-function mutations in genes encoding the Krebs cycle enzymes fumarate hydratase (FH) and succinate dehydrogenase (SDH) cause the accumulation of fumarate and succinate, respectively (6), whereas gain-offunction isocitrate dehydrogenase (IDH) mutations increase levels of D-2-hydroxyglutarate (D-2HG) (7, 8). These metabolites have been implicated in the dysregulation of cellular processes including the competitive inhibition of α-ketoglutarate-dependent (α-KG-dependent) dioxygenase enzymes (also known as 2-oxoglutarate-dependent dioxgenases) and posttranslational modification of proteins (1, 4, 9-11). To date, several lines of biochemical and genetic evidence support roles for fumarate, succinate, and D-2HG in cellular transformation and oncogenesis (3,12).

Exploring cancer metabolism using stable isotope-resolved metabolomics (SIRM)

“…These mutations often result in the production of excess "oncometabolites" that promote activation of proliferative transcription factors and regulate DNA methylation (6). Tracer studies show that SDH-null cells produce citrate predominantly through reductive carboxylation of Gln and accumulate Gln-derived succinate, a product inhibitor of the ␣-KG-dependent dioxygenases, while relying on PC for anaplerosis and synthesis of aspartate to support nucleotide biosynthesis required for proliferation (59,86,87).…”

“…Inactivating mutations in enzymes such as fumarate hydratase (FH) or succinate dehydrogenase (SDH) induce pathophysiological accumulation of substrates that inhibit other critical enzyme functions, whereas less common gain-of-function mutations such as in isocitrate dehydrogenases (IDH) produce metabolites that directly deregulate cellular processes (6). Additionally, cancer cells frequently express fetal isoforms of metabolic enzymes that are subject to different regulatory mechanisms to provide growth advantages (7).…”

Structures of Human ALKBH5 Demethylase Reveal a Unique Binding Mode for Specific Single-stranded N6-Methyladenosine RNA Demethylation

“…4, A and B). The different modes of inhibition caused by a TCA cycle intermediate, such as citrate, may be pathophysiologically relevant because inhibition of some 2OG oxygenases as caused by up-regulation of TCA cycle is proposed to be prooncogenic (54,55).…”

Metabolic control of cancer cell stemness: Lessons from iPS cells

“…Indeed, an invaluable model supporting the notion that certain metabotypic alterations might operate as pivotal molecular events rendering stem cells susceptible to the metabolic rewiring necessary for the acquisition of aberrant stemness and, concurrently, of refractoriness not only to apoptosis but also to differentiation, arises from cancers with a stem cell origin in which gain-of-function mutations in isocitrate dehydrogenase (IDH) generates the oncometabolite 2-hydroxyglutarate (2HG). [124][125][126][127][128][129][130] Because IDH enzymes produce a-ketoglutarate, a cofactor for the TET family of DNA demethylases, neomorphic mutations of IDH that drive the aberrant neosynthesis of the TET inhibitor 2HG can be expected to mostly restrict the "methylation plasticity" that is required for the hierarchical transitions between stem cells and their differentiated progeny. 2HG-induced global hypermethylation prevents the demethylation of genes that are implicated in differentiation, promoting a metabolically-driven increase in the number of stem cells that might occur prior to oncogenic mutations promoting proliferation.…”