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

Caiping Liu,1 Sheng Yang,1 Yanqiu Zhang,2 Chuntao Wang,3 Dandan Du,1 Xian Wang,1 Tong Liu,1 Geyu Liang1 1School of Public Health, Key Laboratory of Environmental Medicine Engineering, Ministry of Education, Southeast University, Nanjing, 210009, Jiangsu, People’s Republic of China; 2Department of Environmental Occupational Health, Taizhou Center for Disease Control and Prevention, Taizhou, 225300, Jiangsu, People’s Republic of China; 3Jiangsu Vocational College of Medicine, Yancheng, 224000, Jiangsu, People’s Republic of ChinaCorrespondence: Geyu Liang Tel +86 25 83272572Fax +86 25 83324322Email lianggeyu@163.comAbstract: 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