Folate-mediated one-carbon metabolism: a targeting strategy in cancer therapy

Chengcan Yang; Jifa Zhang; Minru Liao; Yushang Yang; Yuxi Wang; Yong Yuan; Liang Ouyang

doi:10.1016/j.drudis.2020.12.006

Folate-mediated one-carbon metabolism: a targeting strategy in cancer therapy

Drug Discov Today. 2021 Mar;26(3):817-825. doi: 10.1016/j.drudis.2020.12.006. Epub 2020 Dec 11.

Authors

Chengcan Yang¹, Jifa Zhang¹, Minru Liao¹, Yushang Yang², Yuxi Wang³, Yong Yuan⁴, Liang Ouyang⁵

Affiliations

¹ State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, China.
² State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, China; Department of Thoracic Surgery, West China Hospital, Sichuan University, China.
³ State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, China; Department of Respiratory and Critical Care Medicine, West China Medical School/West China Hospital, Sichuan University, China. Electronic address: yuxiwang@scu.edu.cn.
⁴ State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, China; Department of Thoracic Surgery, West China Hospital, Sichuan University, China. Electronic address: yongyuan@scu.edu.cn.
⁵ State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, China; The Research Units of West China, Chinese Academy of Medical Sciences, China. Electronic address: ouyangliang@scu.edu.cn.

PMID: 33316375
DOI: 10.1016/j.drudis.2020.12.006

Abstract

Folate-mediated one-carbon metabolism (FOCM) supports vital events for the growth and survival of proliferating cells. Nucleotide synthesis and DNA methylation are the biochemical bases of cancers that are highly dependent on FOCM. Recent studies revealed that FOCM is connected with redox homeostasis and epigenetics in cancer. Furthermore, folate-metabolizing enzymes, such as serine hydroxymethyltransferase 2 (SHMT2) and methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), are associated with the development of cancers, including breast cancer, highlighting their potential application in tumor-targeted therapy. Therefore, targeting metabolizing enzymes, especially SHMT2 and MTHFD2, provides a novel strategy for cancer treatment. In this review, we outline current understanding of the functions of SHMT2 and MTHFD2, discussing their expression, potential functions, and regulatory mechanism in cancers. Furthermore, we discuss examples of inhibitors of SHMT2 and MTHFD2.

Publication types

Research Support, Non-U.S. Gov't
Review

MeSH terms

Aminohydrolases / antagonists & inhibitors
Aminohydrolases / metabolism
Animals
Carbon / metabolism
Cell Survival / physiology
DNA Methylation / genetics
Folic Acid / metabolism
Glycine Hydroxymethyltransferase / antagonists & inhibitors
Glycine Hydroxymethyltransferase / metabolism
Humans
Methylenetetrahydrofolate Dehydrogenase (NADP) / antagonists & inhibitors
Methylenetetrahydrofolate Dehydrogenase (NADP) / metabolism
Molecular Targeted Therapy*
Multifunctional Enzymes / antagonists & inhibitors
Multifunctional Enzymes / metabolism
Neoplasms / drug therapy*
Neoplasms / pathology

Substances

MTHFD2 protein, human
Multifunctional Enzymes
Carbon
Folic Acid
Methylenetetrahydrofolate Dehydrogenase (NADP)
Glycine Hydroxymethyltransferase
SHMT protein, human
Aminohydrolases