From Metabolism to Genetics and Vice Versa: The Rising Role of Oncometabolites in Cancer Development and Therapy

Abstract

Over the last decades, the study of cancer metabolism has returned to the forefront of cancer research and challenged the role of genetics in the understanding of cancer development. One of the major impulses of this new trend came from the discovery of oncometabolites, metabolic intermediates whose abnormal cellular accumulation triggers oncogenic signalling and tumorigenesis. These findings have led to reconsideration and support for the long-forgotten hypothesis of Warburg of altered metabolism as oncogenic driver of cancer and started a novel paradigm whereby mitochondrial metabolites play a pivotal role in malignant transformation. In this review, we describe the evolution of the cancer metabolism research from a historical perspective up to the oncometabolites discovery that spawned the new vision of cancer as a metabolic disease. The oncometabolites' mechanisms of cellular transformation and their contribution to the development of new targeted cancer therapies together with their drawbacks are further reviewed and discussed.

Keywords: cancer; epigenetics; metabolism; metabolomics; oncometabolites; therapy.

Figure 1

Oncometabolites production and reactions. Loss of function of mutated SDH and FH enzymes leads to the accumulation of succinate and fumarate that triggers post-translational proteins modifications such as succinylation and succination, respectively. The R-2HG derives mainly from the neomorphic catalytic activity of the mutated mitochondrial IDH2 and cytosolic IDH1, and less from non-canonical reactions involving the PHDGH and HOT enzymes. FH, fumarate hydratase; SDH, succinate dehydrogenase; α-KG, α-ketoglutarate; R-2HG, R-2-hydroxyglutarate; PHDGH, phosphoglycerate dehydrogenase; HOT, hydroxyacid-oxoacid-transhydrogenase; 4-BH, 4- hydroxybutyrate; SSA, succinic semialdehyde; AS, argininosuccinate; ARG, arginine.

Figure 2

Oncometabolites epigenetic and pseudohypoxia effects. Oncometabolites act as competitive inhibitors of αKG-dependent dioxygenases (αKGDDs) such as the KDMs and TETs families responsible for the modulation of chromatin by demethylation of histones and DNA CpG islands, respectively. The inhibition of PHDs blocks the HIF proline hydroxylation for the ubiquitin-proteasome degradation leading to HIF stabilization and activation of the hypoxia signalling pathway establishing a pseudo-hypoxic phenotype. KDMs, lysine histone demethylases; TETs, ten-eleven translocation; K, lysine; C, cytosine; P, proline; PHDs, prolyl hydroxylases; HIF, hypoxia-inducible factor; Ub, ubiquitin.