Emerging Roles of N6-Methyladenosine Demethylases and Its Interaction with Environmental Toxicants in Digestive System Cancers

Abstract

Digestive system cancers are common cancers with high cancer deaths worldwide. They have become a major threat to public health and economic burden. As one of the most universal RNA modifications in eukaryotes, the N6-methyladenosine (m6A) modification is involved in the occurrence, development, prognosis, and treatment response of various cancers, including digestive system cancers. M6A demethylases shape the m6A landscape dynamically, playing important roles in cancers. In addition, accumulating evidence reveal that many environmental toxicants are the established risk factors for digestive system cancers and associated with m6A modification. In this review, we summarize the multiple functions of M6A demethylases (fat mass and obesity-associated protein (FTO), AlkB homolog 5 (ALKBH5) and AlkB homolog 3 (ALKBH3)) in digestive system cancers, which are aberrantly expressed and affect cancer progression. We also discuss the potential roles of m6A demethylases in the assessment of environmental exposure, the signature for prevention and diagnosis of digestive system cancers.

Keywords:

• m6A modification
• FTO
• ALKBH5
• environment toxicants
• digestive system cancers

Acknowledgment

The present study was supported by the National Natural Science Foundation of China (81972998, 81803201, 81673132).

Abbreviations

M6A, N6-methyladenosine; FTO, Fat mass and obesity-associated protein; ALKBH5, AlkB homolog 5; ALKBH3, AlkB homolog 3; N, Nitrogen; A, Adenine; 3ʹ UTR, 3ʹ Untranslated region; MTC, Multicomponent methyltransferase complex; METTL3, Methyltransferase-like 3; METTL14, Methyltransferase-like 14; WTAP, Wilms tumor suppressor-1-associated protein; RBM15, RNA Binding Motif Protein 15; ZC3H13, Zinc finger CCCH domain-containing protein 13; METTL16, Methyltransferase-like 16; METTL5, Methyltransferase-like 5; YTHDFs, YTH N6-Methyladenosine RNA Binding Proteins; IGF2BPs, Insulin-like growth factor 2 mRNA-binding proteins; HNRNPs, Heterogeneous nuclear ribonucleoprotein; HP, Helicobacter pylori; ALKBH9, alkB homolog 9; GWAS, Genome-Wide Association Studies; SNP, Single nucleotide polymorphism; AML, Acute Myeloid Leukemia; GC, Gastric cancer; TCGA, The Cancer Genome Atlas; GEO, Gene Expression Omnibus; IHC, Immunohistochemistry; HCC, Hepatocellular carcinoma; ICC, Intrahepatic cholangiocarcinoma; CRC, Colorectal cancer; PC, Pancreatic cancer; EC, Esophageal cancer; hm6A, N6-hydroxymethyladenosine; f6A, N6-formyladenosine; CB, Carbon black; Cd, Cadmium; PM, Particulate matter; DEHP, Di-(2-Ethylhexyl) phthalate; CSC, Cigarette smoke condensate; AFB1, Aflatoxin B1; ROS, Reactive oxygen species; TCS, Triclosan; BPA, Bisphenol A exposure; DEN, Diethylnitrosam.

Disclosure

The authors declare no financial competing interests or non-financial competing interests in this work.