Crosstalk among m6A RNA methylation, hypoxia and metabolic reprogramming in TME: from immunosuppressive microenvironment to clinical application

Zhang, Fusheng; Liu, Haiyang; Duan, Meiqi; Wang, Guang; Zhang, Zhenghou; Wang, Yutian; Qian, Yiping; Yang, Zhi; Jiang, Xiaofeng

doi:10.1186/s13045-022-01304-5

Table 2 Effects of m⁶A methylation on tumor biological functions

From: Crosstalk among m⁶A RNA methylation, hypoxia and metabolic reprogramming in TME: from immunosuppressive microenvironment to clinical application

Types of tumor biological behavior	m⁶A regulators	Tumor types	Mechanism	Effects on biological behavior of tumors	References
Genomic instability	ALKBH5	Lung cancer	ALKBH5 improves the translation efficiency of FOXM1 mRNA by downregulating m⁶A methylation in FOXM1 mRNA	Promotes proliferation and invasion of lung adenocarcinoma cells under hypoxia	[316]
Genomic instability	METTL3	Lung cancer	METTL3-catalyzed m⁶A methylation mediates HMBOX1 gene downregulation, resulting in telomere dysfunction and inactivation of the p53 signaling pathway	Promotes cancer cell proliferation	[257]
Genomic instability	WTAP	HCC	WTAP downregulation suppresses the m⁶A methylation level, thereby blocking the G2/M phase transition	Mediates HCC occurrence	[317]
Cell cycle	ALKBH5	Renal cell carcinoma	Hypoxia-induced HIF-1α upregulates ALKBH5 expression	High ALKBH5 expression promotes tumor proliferation by increasing the percentage of cells in the G2/M phase	[250]
Cell cycle	METTL3	Uveal melanoma	Overexpression of METTL3 promotes tumor proliferation and colony formation by regulating the G1 phase	Promotes tumor proliferation	[309]
Cell cycle	IGF2BP1	HCC	The lncRNA HCG11 regulates IGF2BP1 to affect the G1 phase of HCC through MAPK signaling	Promotes tumorigenesis	[245]
Cell cycle	IGF2BP1	Renal cell carcinoma	IGF2BP1 promotes G1/S cell cycle transition by stabilizing mRNA	Enhances cell cycle progression and promotes tumor proliferation through m⁶A modifications	[318]
Cell cycle	IGF2BP1	Lung cancer	IGF2BP1 silencing induces cell cycle arrest and apoptosis through downregulation of Netrin-1	Inhibits tumor progression	[244]
Cell cycle	IGF2BP3	Renal cell carcinoma	DMDRMR binds IGF2BP3 to stabilize target genes and enhances cell cycle kinase CDK4 and G1-S phase transition	Promotes tumor progression	[247]
Autophagy	FTO	Kidney cancer	FTO-mediated demethylation prevents the decay of YTHDF2-dependent Unc-51-like kinase 1 mRNA by removing the methyl group from the 3′-UTR region	Promotes tumorigenesis	[226]
Autophagy	ALKBH5	Lung cancer	ALKBH5 improves the translation efficiency of lung cancer cells by decreasing the m⁶A methylation level of ubiquitin-binding enzyme E2C (UBE2C) mRNA	Autophagy is inhibited and accelerates migration and invasion of lung cancer cells	[319]
Autophagy/apoptosis	FTO	Ovarian cancer	FTO accelerates ovarian cancer cell proliferation by inhibiting apoptosis and activating autophagy	Promotes tumor proliferation	[320]
Autophagy	METTL3	Seminoma	Overexpression of METTL3 promotes autophagy and cisplatin resistance in tumors	Supports tumorigenesis and proliferation	[299]
Autophagy	YTHDF1	HCC	Hypoxia-mediated HIF-1α induces expression of YTHDF1, a m⁶A methylation reader, and promotes translation of autophagy-related genes ATG2A and ATG14 in a m⁶A methylation-dependent manner	Accelerates HCC autophagy and malignant tumorigenesis	[81]
Apoptosis	FTO	Colorectal cancer	microRNA-96 promotes anti-apoptosis in tumor cells by regulating the AMPKα2-FTO-m⁶A/MYC axis	Accelerates the growth and metastasis of colorectal cancer	[321]
Apoptosis	ALKBH5	Pancreatic cancer	ALKBH5 activates PER1 through transcription in a m⁶A-YTHDF2-dependent manner	Prevents cancer progression by promoting tumor cell apoptosis	[322]
Apoptosis	METTL14	Pancreatic cancer	Upregulation of METTL14 mediates cisplatin resistance by activating the AMPKα/ERK1/2/mTOR pathway to reduce autophagy and apoptosis	Promotes tumor progression	[233]
Apoptosis	METTL3	Colorectal cancer	METTL3 activates the glycolytic pathway and prevents tumor cell apoptosis by stabilizing the transcriptional translation of this gene	Promotes tumor proliferation	[57]
Angiogenesis	IGF2BP3	Colon cancer	IGF2BP3 binds to mRNA of cyclin D1 (cell cycle G1/S phase checkpoint) and regulates tumor angiogenesis by reading m⁶A methylation in the CDS region to reduce its mRNA stability	Promotes angiogenesis and metastasis in colon cancer	[192]
Angiogenesis	YTHDF3	Breast cancer	YTHDF3 induces the translation of m⁶A-enriched gene transcripts	Promotes breast cancer cell metastasis and invasion	[201]
Angiogenesis	YTHDF2	HCC	YTHDF2 processes the decay of m⁶A-containing interleukin 11 (IL11) and serpin family E member 2 (SERPINE2) mRNAs	Reduction of YTHDF2 contributes to angiogenesis and supports tumor metastasis	[195]
Angiogenesis	METTL3	Gastric cancer	P300-mediated activation of H3K27 acetylation in the METTL3 promoter induces METTL3 transcription, which stimulates m⁶A methylation of HDGF mRNA	Accelerates progression of gastric cancer	[197]
Drug resistance	METTL3	Lung cancer	Regulation of MALAT1-miR-1914-3p-YAP axis	Induces drug resistance and metastasis in lung cancer cells	[167]
Drug resistance	ALKBH5	Ovarian cancer	Overexpression of the ALKBH5-HOXA10 loop activates the JAK2/STAT3 signaling pathway	Induces cisplatin resistance in ovarian cancer	[323]
Drug resistance	METTL3	HCC	m⁶A methylation mediates autophagy in HCC via FOXO3	Promotes HCC sorafenib resistance	[202]
Drug resistance	YTHDF1	Colorectal cancer	YTHDF1 promotes cisplatin resistance by reprogramming GLS1-glutamine metabolism in colorectal cancer	Inhibits tumor cell death	[95]
EMT	METTL3	Leukemia	N6-methyladenosine regulates TGFβ1 expression and secretion to affect epithelial-mesenchymal transition of cancer cells	Promotes tumor progression	[324]
EMT	METTL3	Gastric cancer	METTL3 enhances the stability of ZMYM1 mRNA through m⁶A modification, which, in turn, promotes EMT by recruiting the CtBP/LSD1/CoREST complex to bind and mediate repression of the E-calmodulin promoter	Promotes gastric cancer metastasis	[325]
EMT	YTHDF1/METTL3	HCC	METTL3 and YTHDF1 mediate Snail mRNA translation to enhance EMT	Promotes tumor metastasis	[326]
EMT	METTL3	Lung cancer	The m⁶A methyltransferase METTL3 contributes to Transforming Growth Factor-beta-induced epithelial-mesenchymal transition of lung cancer cells through regulation of JUNB	Promotes tumor metastasis	[327]
EMT	METTL3	Ovarian cancer	METTL3 promotes EMT by regulating AXL translation	Promotes growth and invasion of ovarian cancer	[328]

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