The role of ALDH2 in tumorigenesis and tumor progression: Targeting ALDH2 as a potential cancer treatment

Abstract

A major mitochondrial enzyme for protecting cells from acetaldehyde toxicity is aldehyde dehydrogenase 2 (ALDH2). The correlation between ALDH2 dysfunction and tumorigenesis/growth/metastasis has been widely reported. Either low or high ALDH2 expression contributes to tumor progression and varies among different tumor types. Furthermore, the ALDH2∗2 polymorphism (rs671) is the most common single nucleotide polymorphism (SNP) in Asia. Epidemiological studies associate ALDH2∗2 with tumorigenesis and progression. This study summarizes the essential functions and potential ALDH2 mechanisms in the occurrence, progression, and treatment of tumors in various types of cancer. Our study indicates that ALDH2 is a potential therapeutic target for cancer therapy.

Keywords: 4-HNE, 4-hydroxy-2-nonenal; ALD, alcoholic liver disease; ALDH2; ALDH2, aldehyde dehydrogenase 2; AMPK, AMP-activated protein kinase; Acetaldehyde; BCa, bladder cancer; COUP-TF, chicken ovalbumin upstream promoter-transcription factor; CRC, colorectal cancer; CSCs, cancer stem cells; Cancer; Cancer therapy; DFS, disease-free survival; EC, esophageal cancer; FA, Fanconi anemia; FANCD2, Fanconi anemia protein; GCA, gastric cancer; HCC, hepatocellular carcinoma; HDACs, histone deacetylases; HNC, head and neck cancer; HNF-4, hepatocyte nuclear factor 4; HR, homologous recombination; LCSCs, liver cancer stem cells; MDA, malondialdehyde; MDR, multi-drug resistance; MN, micronuclei; Metastasis; NAD, nicotinamide adenine dinucleotide; NCEs, normochromic erythrocytes; NER, nucleotide excision repair pathway; NF-κB, nuclear factor-κB; NHEJ, non-homologous end-joining; NRF2, nuclear factor erythroid 2 (NF-E2)-related factor 2; NRRE, nuclear receptor response element; NSCLC, non-small-cell lung; NeG, 1,N2-etheno-dGuo; OPC, oropharyngeal cancer; OS, overall survival; OvCa, ovarian cancer; PBMC, peripheral blood mononuclear cell; PC, pancreatic cancer; PdG, N2-propano-2′-deoxyguanosine; Polymorphism; Progression; REV1, Y-family DNA polymerase; SCC, squamous cell carcinoma; TGF-β, transforming growth factor β; Tumorigenesis; VHL, von Hippel-Lindau; ccRCC, clear-cell renal cell carcinomas; εPKC, epsilon protein kinase C.

Graphical abstract

Figure 1

Transcriptional and post-translational level control of ALDH2. PI3K/AKT/mTOR and MEK/ERK pathways are involved in transcriptional control of ALDH2. HDAC1 activated by PI3K/AKT/mTOR/pathway and SET has a role in inhibiting the acetylation of nucleosomes for transcriptional suppression. The activated transcription factors of ALDH2 include NRF2, VHL, HNF-4, RXRs, and FOXM1, which interact with the FP330-3′ element of the promoter region to promote the expression of ALDH2. COUP-TFI and ARP-1 bind to the FP330-5′ element repress the promoter activity of ALDH2. JNK, AMPK, and εPKC can phosphorylate the specific sites of ALDH2 protein for repressing or enhancing its activity. SIRT3 inhibits the enzyme activity of ALDH2 by decreasing its acetylation level. RTKs, receptor tyrosine kinase.

Figure 2

The mechanism of DNA damage repair for ALDH2 deficiency induced DNA damage. The ALDH2 deficiency can lead to acetaldehyde-induced DNA interstrand crosslinks, DNA double-strand breaks (DSB), and tandem mutation, which requires the Fanconi anemia pathway (FA), homologous recombination pathway (HR), Y-family DNA polymerase mediated pathway, classical non-homologous end-joining pathway (NHEJ), alternative non-homologous end-joining repair pathway (Alt-NHEJ), and NER pathway for DNA damage repair. The DNA interstrand crosslinks repair mechanisms involve FA and REV1 pathway. The difference between FA and REV1 pathways is that FA pathway needs to incise for unhooking the crosslink, which leads to DNA strand breaks or abasic sites. However, REV1 repair pathway can operate without excision and promote genome stability. The DSBs repair pathways of acetaldehyde-induced include HR, NHEJ, and Alt-NHEJ. When presents BRCA1/2 mutation or FA pathway inactivation, NHEJ, and Alt-NHEJ pathway are required to repair DSBs and this leads to mutagenesis. NER pathway mediates acetaldehyde-induced tandem mutation repair.

Figure 3

ALDH2 deficiency is related to immune dysfunction and causes HCC and leukemia. The ALDH2 deficiency causes acetaldehyde accumulation which induces liver inflammation, HBV infection persistence, T-cell inactivation, resulting to HCC occurrence. Acetaldehyde accumulation mediates HSC mutation and PBMC micronuclei, and these changes can lead to leukemia.