Table 2 m⁶A methylation in cancer metabolic reprogramming

Glucose metabolism

HK2, GLUT1

m⁶A modification was closely correlated with glycolysis pathway activation in colorectal cancer patients’ tissues. Mechanically, HK2, and GLUT1 were found to be regulated by m⁶A modification and participate in glycolysis activation in colorectal cancer

[17]

PKM2

FTO triggered the m⁶A demethylation of PKM2 mRNA and accelerated the translated production, thus promoting hepatocellular carcinoma tumorigenesis

[96]

PIK3CB

A missense variant rs142933486 in PIK3CB reduced the PIK3CB m⁶A level and facilitated its mRNA and protein expression levels mediated by the m⁶A “writers” complex (METTL3/METTL14/WTAP) and YTHDF2

[97]

EGFR, MEK/ERK signaling

YTHDF2 negatively modulated the EGFR mRNA stability in HCC via its binding the m⁶A site in the EGFR 3′-UTR, which in turn impaired the MEK/ERK pathway and consequently impedes the cell proliferation and growth

[102]

NF-κB signaling

METTL3 positively regulated MYD88 expression through controlling m⁶A methylation status of MYD88-RNA, leading to the activation of NF-κB signaling

[103]

NF-κB signaling

METTL3 activated NF-κB signaling by promoting the expression of IKBKB and RELA through regulating translational efficiency

[94]

AKT signaling

m⁶A methylation normally attenuates AKT activity in the endometrium by promoting the m⁶Adependent translation of PHLPP2 and m⁶A-dependent degradation of transcripts encoding subunits of mTORC2, increasing proliferation and tumorigenicity in endometrial cancer

[14]

AKT signaling

The association between m⁶A and AKT signaling was also confirmed in multiple tumor types including leukemia cells and clear cell renal cell carcinoma

[101, 117]

Lipid metabolism

ACC1, ACLY, DGAT2, EHHADH, FASN, FOXO, PGC1A, and SIRT1

ACC1, ACLY, DGAT2, EHHADH, FASN, FOXO, PGC1A, and SIRT1 were dramatically decreased in livers of hepatocyte-specific METTL3 knockout mice. CD36 and LDLR were also downregulated by improving the expression of FASN through its m⁶A demethylase activity

[106]

SREBP1c, CIDEC

FTO increased lipid accumulation by a novel FTO/SREBP1c/CIDEC signaling pathway in an m⁶A-dependent manner in HepG2 cells

[108]

SREBP1c, FASN, SCD1, ACC1

YTHDF2 could also bind to the mRNA of SREBP1c, FASN, SCD1, and ACC1, to decrease their mRNA stability and inhibit gene expression

[109]

AMPK

m⁶A modification resulted in reduced AMPK activity

[110]

FAM225A

m⁶A was highly enriched within FAM225A and enhanced its RNA stability

[111]

Glutamine metabolism

α-KG

FTO and ALKBH5 are α-KG-dependent dioxygenases and competitively inhibited by the structurally related metabolite D2-HG

[114, 115]