Modulation of host N6-methyladenosine modification by gut microbiota in colorectal cancer

Table 1 Functions of N6-methyladenosine regulators

Types	Regulators	Functions	Ref.
	METTL3	Catalyses m6A modification	[30,31]
	METTL14	Provides structural support and recognizes target RNAs	[30,31]
	WTAP	Contributes to the orientation of MTC	[32,33]
	VIRMA/KIAA1429	Recruits m6A complexes to specialized RNA sites	[32,33]
m6A writers	ZC3H13	Bridges WTAP to Nito	[32,33]
	RBM15	Binds to the m6A complex and recruits to specialized RNA sites	[32,33]
	CBLL1/HAKAI	Contributes to the stabilization of MTC	[32,34]
	METTL16	Catalyses m6A modification	[35]
	FTO	Affects RNA splicing stabilization and deletes m6A modifications	[36]
m6A erasers	ALKBH5	Regulates RNA export and splicing, and deletes m6A modifications	[36]
	IGF2BPs	Enhances mRNA stability and translation	[37]
	YTHDC1	Mediates RNA splicing and export	[38]
	YTHDC2	Enhances target RNA translation and reduces RNA abundance	[39]
	YTHDF1	Enhances mRNA translation	[40]
	YTHDF2	Promotes mRNA degradation	[40]
m6A readers	YTHDF3	Synergizes with YTHDF1 and YTHDF2 to enhance translation and degradation	[40]
	ELF3	Enhances mRNA translation	[41]
	FMR1	Promotes mRNA degradation	[42]
	HNRNPs	Mediates mRNA splicing and translation	[43]
	HNRNPA2B1	Mediates mRNA splicing and miRNA processing	[44]
	ELAL1/HuR	Improve translation efficiency and stability of mRNA	[45]

m6A: N6-methyladenosine.

Table 2 The role of the gut microbiota in colorectal cancer

Gut microbiota	Roles	Functions	Mechanism	Ref.
Coriobacteriaceae	Promote	Tumorigenesis, progression↑	CPT1A-ERK axis	[68]
Clostridioides difficile	Promote	Tumorigenesis↑	Secrete toxin TcdB	[69]
F. nucleatum	Promote	Tumorigenesis, metastasis↑	modulate TME	[70,71]
ETBF	Promote	Progression↑	Suppress the immune responses	[72]
Escherichia coli	Promote	Proliferation, progression↑	Exert toxic effects on DNA	[73]
Enterococcus faecalis	Promote	Tumorigenesis, progression↑	Secrete metabolite biliverdin	[74]
Salmonella enterica	Promote	Tumorigenesis, proliferation↑	Express secretory protein AvrA	[75]
Streptococcus bovis/gallolyticus	Promote	Tumorigenesis, progression↑	Promote inflammatory response	[76]
Blautia producta	Suppress	Tumorigenesis, progression↓	Facilitate the immune surveillance	[77]
Lactobacillus acidophilus, Lactobacillus rhamnosus, and Lactobacillus casei	Suppress	Migration, invasion↓	Reduce abnormal crypt foci	[78]
Roseburia intestinalis	Suppress	Tumorigenesis, proliferation↓	Produce butyrate and induce CD8+ T cells	[79]
Akkermansia muciniphila	Suppress	Proliferation↓	Modulate CD8+ T cells	[80]

TME: Tumour microenvironment; F. nucleatum: Fusobacterium nucleatum.

Table 3 Relationships among N6-methyladenosine, colorectal cancer, and related mechanisms

m6A regulator	Upstream mechanism	Roles	Functions	Mechanism	Ref.
METTL3	Gut microbiota	Oncogene	Glycolysis, chemo-resistance↑	METTL3↑/LDHA↑	[100]
METTL3	Gut microbiota	Oncogene	Proliferation, migration, invasion↑	METTL3↑/m6A↑/YTHDF2↑/CRB3↓/Hippo↓	[55]
METTL3	Gut microbiota	Oncogene	Glycolysis, progression↑	METTL3↑/m6A/GLUT1↑/mTORC1 ↑	[101]
METTL3	Gut microbiota	Oncogene	Invasion, migration↑	METTL3↑/m6A/circ1662↑/YAP1↑/SMAD3↓	[102]
METTL3	F. nucleatum	Suppressor	Metastasis↑	METTL3↓/m6A↓/YTHDF2/KIF26B↑	[24]
METTL16	Gut microbiota	Oncogene	Glycolysis, progression↑	METTL14↑/IGF2BP1/SOGA1↑/PDK4↑	[83]
METTL14	ETBF	Suppressor	Proliferation↑	METTL14↓/m6A/miR-149-3p↓/PHF5A/KAT2A	[88]
METTL14	Gut microbiota	Suppressor	Proliferation, metastasis↑	METTL14↓/m6A↓/YTHDF2↓/lncRNA XIST↑	[103]
METTL14	Gut microbiota	Suppressor	Migration, invasion, metastasis↑	METTL14↓/m6A↓/YTHDF2/SOX4↑	[104]
ALKBH5	H3K27	Oncogene	Glycolysis, progression↓	ALKBH5↓/JMJD8↓/PKM2↓	[105]
ALKBH5		Oncogene	Proliferation, migration, invasion↑	ALKBH5↑/YTHDF2/RAB5A↑	[106]
ALKBH5		Suppressor	Radiosensitivity↑	ALKBH5↑/YTHDF2/circAFF2↑/Cullin-NEDD8↓	[107]
ALKBH5		Suppressor	Proliferation, migration, invasion↓	ALKBH5↑/PHF20↓	[91]
FTO		Oncogene	Chemo-resistance↑	FTO↑/YTHDF2/SIVA1↓	[92]
FTO	miR-96	Oncogene	Tumorigenesis, progression↑	AMPKα2↓/FTO↑/m6A↓/MYC↑	[93]
IGF2BP2	LINC00460	Oncogene	Proliferation, metastasis↑	IGF2BP2-DHX9↑/HMGA1↑	[108]
YTHDF1		Oncogene	Tumorigenesis, metastasis↑	YTHDF1↑/m6A/ARHGEF2↑	[109]
YTHDF2	miR-6125	Oncogene	Proliferation, growth↓	YTHDF2↓/m6A/GSK3β↑	[110]
HNRNPA2B1	MIR100HG	Oncogene	Chemo-resistance, metastasis↑	hnRNPA2B1↑/m6A/TCF7L2↑	[111]

m6A: N6-methyladenosine; F. nucleatum: Fusobacterium nucleatum.

Table 4 Summary of the molecules of action, inhibitory concentration values, and mechanisms of action of existing anticancer drugs for N6-methyladenosine-targeted therapy

Drug	Role in cancer	Cancer type	Target	IC50	Mechanism	Ref.
STM2457	Tumour inhibitor	AML	METTL3	16.9 nM	m6A↓/HOXA1018↓/MYC19↓	[142]
UZH1a	Tumour inhibitor	AML	METTL3	4.6 μM	Inhibits METTL3 catalytic activity and decreases m6A level and mRNA transcription level	[143]
CS1	Tumour inhibitor	AML	FTO		m6A↑/LILRB4↓/MYC↓/CEBPA↓/RARA↑/ASB2↑	[145]
FB23	Tumour inhibitor	AML	FTO	0.8-1.5 μM	m6A↑/MYC↓/CEBPA↓/RARA↑/ASB2↑	[148]
MA	Tumour inhibitor	AML	FTO	17.4 μM	Binds to FTO and inhibits demethylation	[147]
R-2HG	Tumour inhibitor	AML	FTO		m6A↑/FTO↓/MYC↓CEBPA↓	[146]
Rhein	Tumour inhibitor	Liver cancer	FTO/ALKBH5	30 mM	Competitive binding of FTO to substrate binding sites and increased m6A levels	[149]
2-[(1-hydroxy-2-oxo-2-phenylethyl) sulfanyl] acetic acid	Tumour inhibitor	AML	ALKBH5	0.84 μM	Binds ALKBH5 and decreases m6A levels	[150]
4-{[(furan-2-yl) methyl]amino}-1,2-diazinane-3,6-dione	Tumour inhibitor	AML	ALKBH5	1.79 μM	Binds ALKBH5 and decreases m6A levels	[150]

M6A: N6-methyladenosine; IC50: Inhibitory concentration.