DHODH and cancer: promising prospects to be explored

Abstract

Human dihydroorotate dehydrogenase (DHODH) is a flavin-dependent mitochondrial enzyme catalyzing the fourth step in the de novo pyrimidine synthesis pathway. It is originally a target for the treatment of the non-neoplastic diseases involving in rheumatoid arthritis and multiple sclerosis, and is re-emerging as a validated therapeutic target for cancer therapy. In this review, we mainly unravel the biological function of DHODH in tumor progression, including its crucial role in de novo pyrimidine synthesis and mitochondrial respiratory chain in cancer cells. Moreover, various DHODH inhibitors developing in the past decades are also been displayed, and the specific mechanism between DHODH and its additional effects are illustrated. Collectively, we detailly discuss the association between DHODH and tumors in recent years here, and believe it will provide significant evidences and potential strategies for utilizing DHODH as a potential target in preclinical and clinical cancer therapies.

Keywords: Cancer metabolism; DHODH inhibitors; De novo pyrimidine biosynthesis; Dihydroorotate dehydrogenase; Mitochondria.

Fig. 1

Pyrimidine de novo biosynthesis pathway

Fig. 2

DHODH and mitochondrial respiratory chain. The mammalian mitochondrial electron transport chain comprises four enzyme complexes located in the mitochondrial inner membrane: complexes I, II, III, and IV. Complexes I and II transfer reducing equivalents from NADH and succinate to complex III via the ubiquinone pool, respectively, and complex III further transfers these equivalents to complex IV through cytochrome c. Electrons from complex IV are eventually transferred to dioxygen, subsequently producing water. ATP synthase generates ATPs by oxidative phosphorylation utilizing the transmembrane electrochemical gradient maintained by proton pumping activities of complexes I, III, and IV [36]. DHODH converts dihydroorotate to orotate, generating electrons that are transferred via redox-cycling of ubiquinone to complex III [2]. Thus, the de novo synthesis of pyrimidine nucleotides is coupled to the mitochondrial respiratory chain via DHODH [47]. Abbreviations: CI, complex I; CII, complex II; CIII, complex III; CIV, complex IV; CV, complex IV; FAD, flavin adenine dinucleotide; FMN, flavin mononucleotide. Q, coenzyme Q (CoQ), so known as ubiquinone; QH₂, the hydroquinone (antioxidant) form of CoQ, also known as ubiquinol; UMP, uridine monophosphate

Fig. 3

DHODH mRNA level in different malignancy types. The chart shows DHODH mRNA level in different kinds of malignancies. A circle represents a sample. All these data are concluded in Cbioportal, from TCGA Pan-Cancer Atlas Studies which cover 10967 samples from 32 studies

Fig. 4

DHODH co-expressed genes. a Co-expression genes network with DHODH. b Relationship between DHODH co-expressed genes and different cancers. c The top 20 co-expressed genes with DHODH are ranked by sum of their LLS score. d Positively correlated top 20 pathways to DHODH co-expression genes by GeneSet analysis. Enriched terms by p value < 0.05. All these data are concluded from database Coexpedia. Abbreviations: ACRV1, acrosomal vesicle protein 1; CYP2C9, cytochrome P450 family 2 subfamily C member 9; PAPPA2, pappalysin 2; NTRK3, neurotrophic tyrosine kinase, receptor, type 3; DCT, dopachrome tautomerase; CA12, arbonic anhydrase XII; DRD2, dopamine receptor D2; WNT6, wingless-type MMTV integration site family member 6; PAX8, paired box 8; CYP2A6, cytochrome P450 family 2 subfamily A member 6; HFE, hemochromatosis; UBE2D4, ubiquitin conjugating enzyme E2D 4 (putative); EGFR, epidermal growth factor receptor; SIGLEC6, sialic acid binding Ig-like lectin 6; ETV1, ets variant 1; MID2, midline 2; EXPH5, exophilin 5; ATP10B, ATPase, class V, type 10B; SLC30A3, solute carrier family 30 (zinc transporter), member 3; ALDOB, aldolase, fructose-bisphosphate B

Fig. 5

DHODH co-expressed proteins. a Co-expressed proteins with DHODH. b GO analysis concludes the top 20 biological process of proteins/genes co-expressed with DHODH. c KEGG analysis reveals the related pathways of proteins/genes co-expressed with DHODH. All these data are from STRING, which is a website used for protein-protein interaction network and functional enrichment analysis

Fig. 6

Mutation and alternation of DHODH. a All these data are from Cbioportal. b DHODH post-translational modifications (PTMs) sites, which are available for the Ensembl transcript ENST00000219240. Mutation diagram circles are colored with respect to the corresponding mutation types. In case of different mutation types at a single position, color of the circle is determined with respect to the most frequent mutation type. Mutation types and corresponding color codes are as follows: green, missense mutations; black, truncating mutations (nonsense, nonstop, frameshift deletion, frameshift insertion, splice site); brown, inframe mutations (inframe deletion, inframe insertion). All these data are from Cbioportal. c An overview of the types of DHODH mutation distribution. All these data are from COSMIC