Zhao Y, Feng F, Guo QH, Wang YP, Zhao R. Role of succinate dehydrogenase deficiency and oncometabolites in gastrointestinal stromal tumors. World J Gastroenterol 2020; 26(34): 5074-5089 [PMID: 32982110 DOI: 10.3748/wjg.v26.i34.5074]
Corresponding Author of This Article
Yue Zhao, MD, Doctor, Department of Gastroenterology, The First Hospital of Lanzhou University, Key Laboratory for Gastrointestinal Disease of Gansu Province, No. 1 Donggaung West Road, Lanzhou 730000, Gansu Province, China. ldyy_yzhao@lzu.edu.cn
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
Review
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Yue Zhao, Qing-Hong Guo, Yu-Ping Wang, Department of Gastroenterology, the First Hospital of Lanzhou University, Key Laboratory for Gastrointestinal Disease of Gansu Province, Lanzhou 730000, Gansu Province, China
Fei Feng, Department of Ultrasound, the First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
Rui Zhao, Department of Biochemistry and Molecular Genetics, School of Medicine, the University of Alabama at Birmingham, Birmingham, AL 35294, United States
Author contributions: All authors contributed to concept development and reference collection; Zhao Y and Zhao R designed the overall study and jointly wrote the manuscript.
Supported byScience and Technology Program of Gansu Province Grant, No. 18JR3RA339 and No. 18JR3RA363; Fund of the First Hospital of Lanzhou University Grant, No. ldyyyn2018-63; Teaching and Research Project of the First Clinical Medical College of Lanzhou University in 2018 Grant, No. 2018007; NIH awards, No. R21NS106430 and No. R01OD026594; Cystic Fibrosis Foundation Research Grant, No. ZHAO19G0; an American Cancer Society-IRG Junior Faculty Development Grant, a UAB CCC Neuro-oncology Research Acceleration Grant, and a UAB Faculty Development Grant Program Award.
Conflict-of-interest statement: All authors have no any conflict of interests.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Yue Zhao, MD, Doctor, Department of Gastroenterology, The First Hospital of Lanzhou University, Key Laboratory for Gastrointestinal Disease of Gansu Province, No. 1 Donggaung West Road, Lanzhou 730000, Gansu Province, China. ldyy_yzhao@lzu.edu.cn
Received: May 27, 2020 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 Processing time: 104 Days and 19.5 Hours
Abstract
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.
