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

Figures & data

Figure 1 The dynamics and reversible process of m6A modification. M6A is reversed by m6A demethylases (FTO, ALKBH5 and ALKBH3) and plays important roles in digestive system cancers.

Table 1 The Role of FTO in Human Digestive System Cancers

Cancer Types	Roles	Expression	Target	Molecular Mechanism	References
Gastric cancer	Oncogene	Up	MYC	HDAC3 mediated FTO/m6A/myc axis to regulate FOXA2 in GC initiating activities.	[^Citation40]
Intrahepatic cholangiocarcinoma	Suppressor	Down	GNAO1	Depleted FTO by SIRT1 promoted m6A+ levels of HCC tumor suppressor GNAO1 and decreased its mRNA expression.	[^Citation46]
Hepatocellular carcinoma	Oncogene	Up	PKM2	FTO triggered the demethylation of PKM2 mRNA and accelerated the translated production.	[^Citation47]
Hepatocellular carcinoma	Suppressor	–	Cul4a	FTO-dependent m6A regulated of Cul4a mRNA to play protective function in the initiation of HCC development.	[^Citation49]
Colorectal cancer	Oncogene	Up	PD-L1	FTO mediated m6A regulated PD-L1 expression that might affect a therapeutic response to immunotherapy.	[^Citation50]
Colorectal cancer	Oncogene	Up	MYC	MiR-96 could potentially stimulate malignancy and aggressiveness of CRC by activating AMPKα2-mediated FTO/MYC.	[^Citation51]
Pancreatic cancer	Oncogene	Up	c-MYC	FTO enhanced stability of MYC and bHLH via decreasing m6A level.	[^Citation55]
Esophageal squamous cell carcinoma	Oncogene	Up	MMP13	FTO facilitated cell proliferation and migration by up-regulating MMP13.	[^Citation57]

Table 2 The Role of ALKBH5 in Human Digestive System Cancers

Cancer Types	Roles	Expression	Target	Molecular Mechanism	References
Gastric cancer	Oncogene	Up	NEAT1	ALKBH5 promoted GC invasion and metastasis by demethylating the lncRNA NEAT1.	[^Citation60]
Colon cancer	Suppression	Down	–	Overexpression of ALKBH5 inhibited colon cancer cells invasion in vitro and metastasis in vivo.	[^Citation64]
Colon cancer	Oncogene	Up	NEAT1	ALKBH5-NEAT1 axis might regulate malignant behavior.	[^Citation65]
Pancreatic cancer	Suppression	Down	WIF-1	ALKBH5 repressed PDAC tumorigenesis by reducing m6A levels of WIF-1 and hindering activation of Wnt signaling.	[^Citation69]
Pancreatic cancer	Suppression	Down	PER1	ALKBH5 activated PER1 by m6A demethylation in an m6A-YTHDF2-dependent manner and P53-induced activation of ALKBH5 transcription acted as a feedback loop regulating the m6A modifications in PC.	[^Citation70]
Pancreatic cancer	Suppression	Down	KCNK15-AS1	ALKBH5 mediated m6A to regulate KCNK15-AS1 and affect its stability.	[^Citation71]
Hepatocellular carcinoma	Suppressor	Down	LYPD1	Down-regulation of ALKBH5 activated the m6A machinery contributing to the epigenetic activation of LYPD1 which is recognized and stabilized by IGF2BP1.	[^Citation75]
Esophageal squamous cell carcinoma	Suppressor	Down	Pri-miR-193a-3p	ALKBH5 mediated m6A modification to regulate the pri-miR-193-3p processing which suggested a positive feedback loop between miR-193-3p and ALKBH5.	[^Citation77]
Esophageal squamous cell carcinoma	Oncogene	Up	CDKN1A	Depletion of ALKBH5 increased m6A methylation and stability of CDKN1A mRNA, leading to up-regulation of p21 (CDKN1A) protein expression.	[^Citation78]

Figure 2 The mechanism and functions of m6A demethylases FTO and ALKBH5 involved in human digestive system cancers.

Figure 3 Effect of m6A modification on human diseases by environmental toxicants exposures.

Table 3 The Role of Demethylase in Digestive System Cancers Induced by the Environmental Toxicants

Environmental Toxicants	Disease Type	M6A Methylation Levels	Alter of M6A Associated Proteins	Function and Mechanism	References
CB	Pulmonary fibrosis	Decreased	Down: METTL3/METTL14	The constructed METTL3/METTL14-m6A- miRNA126- PI3K/AKT/mTOR axis might serve as a biomarker for pulmonary fibrosis prevention.	[^Citation84]
Cd	Ovarian injury	Decreased	–	After Cd exposure, expression of miR-92a-2-5p was upregulated, which may be primarily related to upregulation of c-MYC.	[^Citation85]
CB	Cardiovascular disease/ lung function	Increased	Air pollutants were not associated with m6a gene expression levels	–	[^Citation86]
Smoking	Cardiovascular Disease/ lung function	Decreased	METTL3 was positively associated with men smoking less than 3.8 pack years	–	[^Citation86]
NaAsO2	Cancer	Increased	Up: METTL3/METTL14/WTAP Down: FTO	M6A-mediated miRNAs can regulate pathways which are closely associated with cellular proliferation and apoptosis.	[^Citation87]
NaAsO2	Cancer	Increased	Hormesis effects	The reversible m6A modification is associated with the arsenite-driven hormesis on cytotoxicity.	[^Citation88]
PM	Lung adenocarcinoma	Decreased	Up: METTL3/WTAP/FTO/ALKB/ HNRNPC	M6A RNA methylation can be modified by exposure to environmental toxicants.	[^Citation89]
CoCl2	Nervous damage	Decreased	Up: WTAP (cell) Down: METTL3/ METTL14/FTO/ALKBH5 (cell) Up: METTL3/METTL14/WTAP (rat) Down: FTO/ALKBH5 (rat).	m6A modification in neurodegenerative disease-associated genes upon CoCl2. exposure and identified regulatory strategy between m6A and potential targets mRNA.	[^Citation90]
DEHP	Prepubertal testicular injury	Increased	Up: YTHDC2 Down: FTO	M6A modification of Nrf2 mRNA increased upon DEHP exposure.	[^Citation91]
Arsenic	Arsenical keratoses (including skin cancer)	Increased	Down: FTO	FTO forms a positive feedback loop with autophagy inhibition to maintain FTO accumulation in arsenic tumorigenesis.	[^Citation92]
CSC	Pancreatic cancer	Increased	Up: METTL3	Cigarette smoke-induced miR-25-3p excessive maturation via m6A modification promotes the development and progression of PC.	[^Citation93]
AFB1	Liver diseases	Increased	Up: METTL3 Down: FTO/YTHDF2	AFB1-induced ROS accumulation changed m6A modification and resveratrol played protective role in alleviating hepatic disorder induced by AFB1.	[^Citation94]
TCS	Metabolic disorder	Decreased	Up: FTO/YTHDF1/YTHDC1 Down: METTL3	EDCs exposure led to the decreased global m6A level and abnormal expression of m6A modulators in zebrafish larvae.	[^Citation95]
BPA			Up: YTHDF1/YTHDC1
DEN	Hepatocellular carcinoma	-	Down: FTO	FTO might target Cul4a mRNA to decrease Cul4a protein levels, thereby presumably blocking cell cycle progression and proliferation.	[^Citation49]

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