m6A modification: recent advances, anticancer targeted drug discovery and beyond

Deng, Li-Juan; Deng, Wei-Qing; Fan, Shu-Ran; Chen, Min-Feng; Qi, Ming; Lyu, Wen-Yu; Qi, Qi; Tiwari, Amit K.; Chen, Jia-Xu; Zhang, Dong-Mei; Chen, Zhe-Sheng

doi:10.1186/s12943-022-01510-2

Molecular Cancer

Table 1 The effects and mechanisms of m6A modification regulators on tumor progression

From: m6A modification: recent advances, anticancer targeted drug discovery and beyond

Cancer Type	Type	m6A regulator	Related factor	Function	Ref.
AML	Writer	METTL3	CEBPZ, SP1	Maintains the leukemic state	[54]
		METTL3	C-MYC, BAL2, PTEN	Inhibits differentiation and increases cell growth	[55]
		METTL14	MYB, MYC	Inhibits myeloid differentiation and enhance self-renewal of leukemia stem/initiation cells	[56]
	Eraser	FTO	ASB2, RARA	Promotes cell transformation and leukemogenesis, and inhibits leukemia cell differentiation	[57]
			MYC, CEBPA	Induces tumorigenesis	[58]
			LILRB4	Maintains cancer stem cell self-renewal and contributes to immune evasion	[59]
		ALKBH5	TACC3	Contributes to poor prognosis, maintenance of AML and self-renewal of leukemia stem/initiating cells	[60]
	Reader	YTHDF2	Tnfrsf2	Maintenance of leukemic stem cells	[61]
	Reader	IGF2BP1	LIN28B, let-7a	Enhances tumorigenicity	[62]
BC	Writer	METTL3	HBXIP, let-7 g	Accelerates cell proliferation in BC and promotes cancer progression	[63]
			P21	Contributes to worse prognosis and shorter disease-free survival and promote proliferation of cancer cell	[64]
			Adenylate kinase 4 (AK4)	Contributes to tamoxifen resistance	[65]
			Pri-mi-221-3p	Promotes adriamycin resistance	[66]
			ERRγ, ESRRG	Induces chemoresistance of cancer cell	[67]
	Eraser	FTO	BNIP3	Contributes to poor prognosis, promotes cancer cell proliferation, colony formation and metastasis	[68]
	Eraser	FTO	MiR-181b-3p, ARL5B	Promotes invasion and migration of cancer cell	[69]
	Reader	YTHDF2	MYC	Upregulated in TNBC, depletion of YTHDF2 suppresses tumor growth, triggers activation of EMT, initiate apoptosis, and sensitizes TNBC cells to proteotoxic	[37]
		YTHDF3	ST6GALNAC5, GJA1, EGFR	Contributes to breast cancer brain metastasis and poor survival	[70]
		KIAA1429	CDK1	Contributes to shorter overall survival of patients and promotes cancer cell proliferation and metastasis	[71]
		IGF2BP1	LncRNA KB-1980E6.3, c-Myc	Maintains the stemness of breast cancer cells and tumorigenesis	[72]
		HNRNPA2B1	Erα, miR-222-3p	Induces acquired endocrine-resistance	[73]
BLC	Writer	METTL3	Pri-miR221/222, PTEN	Contributes to poor prognosis of BLC patients and promotes tumor cell proliferation	[74]
		METTL3	AFF4, IKBKB, RELA, MYC	Promotes cancer progression	[75]
		METTL14	Notch1	Inhibits bladder tumor initiating cells self-renewal and bladder tumorigenesis	[76]
	Reader	IGF2BP1	MYC, FSCN1, circPTPRA	Promotes BLC growth and aggressiveness in vivo and in vitro	[77]
CRC	Writer	METTL3	MiR-1246, SPRED2, MAPK pathway	Contributes to tumor metastasis	[78]
			GLUT1, mTORC1 signaling	Contributes to poor survival and promote CRC initiation and progression	[79]
			SOX2	Contributes to poor prognosis, cell self-renewal, stemness, migration, tumorigenesis and metastasis	[80]
			HK2, SLC2A1	Drives glycolytic metabolism, promotes tumorigenesis	[81]
			Circ1662	Promotes CRC cell invasion and migration	[82]
		METTL14	Pri-miR-375	Inhibits CRC cell growth and metastasis	[83]
			SOX4	Inhibits CRC cells migration, invasion and metastasis	[84]
			LncRNA XIST	Suppresses proliferation and metastasis	[51]
		METTL3/METTL14	STAT1, IRF1	Regulates immune responses to anti-PD-1 therapy	[85]
	Eraser	FTO	MYC	Promotes cancer progression	[86]
	Reader	YTHDF1	FZD9, WNT6	Promotes tumorigenicity and regulates stem cell-like activity	[87]
		YTHDF2	GASK3β, miRNA-6125	Promotes cancer growth	[88]
		YTHDF3	YAP, lncRNA GAS5	Contributes to poor overall survival, promotes CRC cell proliferation, invasion, metastasis	[89]
		IGF2BP1	RBRP, c-Myc	Promote tumorigenesis	[90]
		IGF2BP2	LINC00460, DHX9, HMGA1	Promote tumor progression	[91]
		IGF2BP3	CCND1, VEGF	Associates with cancer progression and survival, regulates cell cycle and angiogenesis	[92]
EC	Writer	METTL3/METTL14	PHLPP2, AKT, mTOR	Promotes cell proliferation and tumorigenicity	[93]
GBM	Writer	METTL3	SRSF, BCL-X, NCOR2	Promotes the growth and self-renewal of glioma stem cells	[94]
			ADAR1, CDK2	Contributes to tumorigenesis	[95]
			SOX2, HuR	Induces resistance to γ-irradiation and promotes DNA repair	[96]
	Eraser	FTO	–	Promotes glioma stem cell (GSC) growth and self-renewal	[97]
	Eraser	ALKBH5	FOXM1	Enhances self-renewal and tumorigenesis of GBM stem-like cell	[98]
	Reader	YTHDF2	EGFR, SRC, ERK, LXRA, HIVEP2	Contributes to poor prognosis, promotes GBM cell proliferation, invasion, and tumorigenesis.	[99]
GC	Writer	METTL3	LncRNA ARHGAP5-AS1, ARHGAP5	Promotes chemoresistance	[100]
			PTEN, TMEM127, pri-miR-17–92	Contributes to poor prognosis and enhance sensitivity to everolimus	[101]
			HDGF	Contributes to poor prognosis, promote cancer cell proliferation, liver metastasis, angiogenesis, glycolysis	[102]
			BATF2	Promotes tumor progression and metastasis	[103]
			ZMYM1	Promotes EMT program and metastasis	[104]
		KIAA1429	C-Jun	Promotes cancer cell proliferation	[105]
	Eraser	FTO	–	Promotes proliferation and migration of cancer cell	[106]
	Eraser	ALKBH5	LncRNA NEAT1	Promotes invasion and metastasis	[107]
	Reader	YTHDF1	FZD7	Contributes to aggressive tumor progression and poor overall survival, promotes proliferation and tumorigenesis	[108]
HCC	Writer	METTL3	CTNNB1, Wnt/β-catenin pathway	Promotes tumor progression	[109]
			LINC00958	Promotes tumor progression	[110]
			SOCS2	Contributes to poor prognosis of patients with HCC, promotes HCC growth	[111]
		METTL14	DGCR8, miRNA 126	Inhibits tumor metastasis	[112]
		WTAP	HuR, p21/27, Ets-1	Contributes to poor prognosis and contributes to the progression of HCC	[113]
		KIAA1429	GATA3, lncRNA GATA3-AS	Contributes to poor prognosis, promote tumor growth and metastasis	[114]
	Eraser	FTO	SIRT1	Inhibits cancer tumorigenesis	[115]
	Eraser	ALKBH5	LYPD1, IGF2BP1	Suppresses cancer cell proliferation and invasion	[116]
	Reader	YTHDF1	HIF-1α, ATG2A, ATG14	Contributes to poor prognosis, promotes autophagy and autophagy-related malignancy	[117]
		YTHDF1	EGFR	Promotes cell viability and metastasis	[118]
		YTHDF2	MiR-145	Contributes to malignancy of HCC	[119]
		YTHDF2	IL11, SERPINE2	Suppresses tumor growth, vasculature remodeling and metastasis	[120]
HNSCC	Writer	METTL3/METTL14	LNCAROD	Promote malignant development in HNSCC	[121]
		METTL3	CircCUX1	Contributes to radiotherapy resistance in HSCC	[122]
			ZNF750	Modulates NPC progression	[123]
			YTHDF1, c-Myc	Promotes the proliferation, invasion, migration tumor growth in OSCC progression	[124]
			BMI1	Contributes to poor prognosis, promotes OSCC proliferation, self-renewal, tumor growth and metastasis	[125]
		RBM15	TMBIM6, IGF2BP3	Contributes to unfavorable prognosis, promotes the proliferation, invasion, migration, and apoptosis of LSCC	[126]
	Reader	HNRNPA2B1	LINE-1, TGF-β1, Smad2, Slug	Contributes to poor overall survival, promotes OSCC tumorigenesis and metastasis	[127]
		YTHDC2	IGF1R, AKT, S6	Promote radiotherapy resistance in NPC	[128]
		YTHDF1	TFRC	Promote HSCC tumorigenesis	[129]
LC	Writer	METTL3	LncRNA LCAT3	Modulates LC progression	[130]
			MiR-143-3p	Promotes brain metastasis of LC	[131]
			MALAT1-miR-1914-3p-YAP axis	Contributes to drug resistance and metastasis	[132]
			TAZ, EGFR	Promotes LC growth, survival, and invasion	[133]
	Reader	IGF2BPs	CircNDUFB2	Promotes tumor progression and metastasis, modulates immune responses	[134]
		HNRNPA2B1	LncRNA 01234	Promote cancer cell growth and inhibit apoptosis	[135]
		YTHDF1	Keap1-Nrf2-AKR1C1 axis	Contributes to hypoxia adaptation and pathogenesis of NSCLC	[136]
MEL	Eraser	FTO	IFNγ, PD-1, CXCR4, SOX10	Promotes tumorigenesis and anti-PD-1 resistance	[137]
	Reader	YTHDF1	HINT2	Inhibits tumor progression	[138]
	Reader	YTHDF2	PER1, TP53	Accelerates tumorigenesis of ocular MEL	[139]
MM	Eraser	FTO	HSF1	Promotes MM proliferation, migration, and invasion	[140]
MM	Reader	HNRNPA2B1	AKT3, ILF3	Contributes to unfavorable prognosis, promotes tumor progression	[141]
OC	Writer	METTL3	PTEN, PI3K, Akt, mTOR, miR-126-5p	Promotes the progression and tumorigenesis	[142]
	Writer	WTAP	MAPK, AKT	Contributes to worse survival outcome and promote tumor progression	[143]
	Eraser	FTO	cAMP signaling	Inhibits tumorigenesis and ovarian cancer stem cell self-renewal	[144]
	Eraser	ALKBH5	NANOG	Promotes tumor progression	[145]
	Reader	YTHDF2	FBW7, BMF	Promotes tumor progression	[146]
		IGF2BP1	SRF1, PDLIM7, FOXK1	Promotes tumor progression and correlates with poor prognosis	[147]
		YTHDF1	EIF3C	Contributes to adverse prognosis, promotes tumorigenesis and metastasis	[148]
OS	Writer	WTAP	HMBOX1	Promotes osteosarcoma growth and metastasis	[149]
OS	Eraser	ALKBH5	YAP, pre-miR-181b-1	Suppresses cell growth, migration, invasion, and triggers cell apoptosis.	[150]
PAAD	Writer	METTL3	PHLPP2, Akt, miR-25-3p	Promotes the initiation and progression of cancer	[151]
		METTL14	PERP	Promotes cancer cell proliferation and migration	[152]
		WTAP	WTAPP1, Wnt signaling	Induces malignant phenotypes of cancer	[153]
	Eraser	FTO	PJA2	Suppresses the proliferation, invasion, and metastasis	[154]
		ALKBH5	PER1, YTHDF2	Inhibits cancer cell proliferation, migration, invasion, tumor growth	[155]
		ALKBH5	WIF-1, Wnt pathway	Sensitizes to chemotherapy and inhibits cancer cell proliferation, migration and invasion	[156]
	Reader	YTHDC1	MiR-30d	Contributes to favorable prognosis, and represses pancreatic tumorigenesis	[157]
	Reader	IGF2BP2	LncRNA DANCR	Contributes to poor outcome and promotes cancer cell proliferation	[158]
PRAD	Writer	METTL3	GLI1	Promotes cell proliferation, survival, colony formation, and invasion	[159]
	Writer	METTL3	MYC	Contributes to poor prognosis, promote development and progression of cancer	[160]
	Reader	YTHDF2	LHPP, NKX3–1	Contributes to poor prognosis and inhibit proliferation and migration of cancer	[38]
RB	Writer	METTL3	PI3K, AKT, mTOR, P70S6K, 4EBP1	Promotes tumor progression	[161]
RCC	Writer	METTL14	BPTF	METTL14 deficiency promoted RCC metastasis	[162]
	Eraser	FTO	SLC1A5	Contributes to the growth and survival of cancer cell	[163]
	Reader	IGF2BP3	DMDRMR, CDK4, COL6A1, LAMA5, FN1	Contributes to poor outcomes and promotes cell proliferation	[164]
TGCT	Writer	VIRMA	–	Contributes to tumor progression and cisplatin resistance	[165]

EC Endometrial cancer, GSC Glioblastoma stem cell, HSCC Hypopharyngeal squamous cell carcinoma, LSCC Laryngeal squamous cell carcinoma, MEL Melanoma, NPC Nasopharyngeal carcinoma, NSCLC Non-small-cell lung carcinoma, OSCC Oral squamous cell carcinoma, TGCTs Testicular germ cell tumors, TNBC Triple negative breast cancer

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