Published online Sep 14, 2020. doi: 10.3748/wjg.v26.i34.5074
Peer-review started: May 28, 2020
First decision: June 4, 2020
Revised: June 14, 2020
Accepted: August 22, 2020
Article in press: August 22, 2020
Published online: September 14, 2020
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. At the molecular level, GISTs can be categorized into two groups based on the causative oncogenic mutations. Approximately 85% of GISTs are caused by gain-of-function mutations in the tyrosine kinase receptor KIT or platelet-derived growth factor receptor alpha (PDGFRA). The remaining GISTs, referred to as wild-type (WT) GISTs, are often deficient in succinate dehydrogenase complex (SDH), a key metabolic enzyme complex in the tricarboxylic acid (TCA) cycle and electron transport chain. SDH deficiency leads to the accumulation of succinate, a metabolite produced by the TCA cycle. Succinate inhibits α-ketoglutarate-dependent dioxygenase family enzymes, which comprise approximately 60 members and regulate key aspects of tumorigenesis such as DNA and histone demethylation, hypoxia responses, and m6A mRNA modification. For this reason, succinate and metabolites with similar structures, such as D-2-hydroxyglutarate and fumarate, are considered oncometabolites. In this article, we review recent advances in the understanding of how metabolic enzyme mutations and oncometabolites drive human cancer with an emphasis on SDH mutations and succinate in WT GISTs.
Core Tip: The connection between altered cellular metabolism and tumorigenesis has gained increased attention in recent years. Deficiency in succinate dehydrogenase (SDH), a key metabolic enzyme, drives tumorigenesis of a subset of gastrointestinal stromal tumors (GISTs) by accumulating the oncometabolite succinate. Oncometabolites such as succinate, D-2-hydroxyglutarate, and fumarate competitively inhibit the α-ketoglutarate-dependent dioxygenase family enzymes, which regulate epigenetic status, hypoxia responses, RNA metabolism, and DNA damage repair. In this article, we review the recent advances in understanding how metabolic enzyme mutations and oncometabolites drive human cancer with an emphasis on the SDH deficiency and succinate in GISTs.