Alterations of metabolic genes and metabolites in cancer

Abstract

Altered metabolic regulation has long been observed in human cancer and broadly used in the clinic for tumor detection. Two recent findings--the direct regulation of metabolic enzymes by frequently mutated cancer genes and frequent mutations of several metabolic enzymes themselves in cancer--have renewed interest in cancer metabolism. Supporting a causative role of altered metabolic enzymes in tumorigenesis, abnormal levels of several metabolites have been found to play a direct role in cancer development. The alteration of metabolic genes and metabolites offer not only new biomarkers for diagnosis and prognosis, but also potential new targets for cancer therapy.

Figure 1. The substrates and regulation by metabolites of α-KG dependent dioxygenases

(A) A schematic diagram of hydroxylation reaction catalyzed by the α-KG dependent dioxygenases. The substrates of this family of enzymes include both nucleic acids and proteins. Five different amino acid residues, Proline (Pro), methyllysine (Lys), methylargnine (Arg), Asparagine (Asn) and Aspartate (Asp), have been found to date to be hydroxylated. Hydroxylation of both Arg and Lys occur only on the methylated, but not unmodified residues. Four bases in DNA or RNA can be methylated by either enzyme (DNA methyltransferase)-catalyzed methylation at C-3 position of cytosine (3-meC) or alkylating agents on a variety positions of different bases. Hydroxylation of methylguanine has been reported for bacterial AlkB, but not for human AlkB homologues (ABH). (B) The currently known oncometabolites (2-HG, succinate, fumarate) act upon a wide range of α-KG dependent dioxygenases both in the cytosol and in the nucleus. In addition to the hydroxylation of protein and DNA substrates, a member of α-KG dependent dioxygenases, fat mass and obesity (FTO) protein, can recognize and hydroxylate N6-methyadenosine in nuclear RNA [102].