Roles of N6‐Methyladenosine Demethylase FTO in Malignant Tumors Progression

Figures & data

Figure 1 m6A dynamic regulation and FTO’s functions.

Table 1 Expression of FTO as Oncogene or Tumor Suppressor Gene in Different Tumors

Cancers	Expression	Biological Functions	Target/Pathway	References
Leukemia	Up	Promote the survival and proliferation of AML cells, and inhibit apoptosis	MYC/CEBPA	[^Citation66]
		Promote leukemia cell viability, transformation and leukemogenesis	ASB2/RARA	[^Citation31]
Breast cancer	Up	Promote the proliferation, colony formation and metastasis of breast cancer cell, Promote energy metabolism	PI3K/AKT	[^Citation35]
		Inhibit apoptosis of breast cancer cells	BNIP3	[^Citation34]
Lung cancer	Up	Promote the proliferation and invasion of lung cancer cells and inhibit the apoptosis of tumor cells	MZF1	[^Citation41]
			USP7	[^Citation42]
Cervical cancer	Up	Play an important role in the regulation of the proliferation and migration of cervical cancer cells	E2F1	[^Citation49]
			MYC
Endometrial carcinoma	Up	Enhance endometrial cancer cells proliferation and invasion	PI3K/AKT	[^Citation36]
			MAPK
Glioblastoma	Up	Promote the growth and self-renewal of glioblastoma stem cells and involve in the proliferation of oligodendrocyte progenitor cells (OPCs)	_	[^Citation38]
Pancreatic cancer	Up	Promote pancreatic cancer cell proliferation and inhibit apoptosis	c-MYC	[^Citation46]
Gastric cancer	Up	Promote the proliferation, migration and invasion of gastric cancer cell lines	_	[^Citation44]
Hepatocellular cancer	Up	Overexpression of FTO predict a lower survival rate in patients	PKM2	[^Citation57]
	Down	Play a protective function in liver carcinogenesis		[^Citation60,Citation61]
Clear cell renal carcinoma	Down	Play a critical anti-tumorigenic role in clear cell renal cell carcinoma	PGC-1α	[^Citation62]
Ovarian cancer	Down	Inhibit the self-renewal of ovarian stemness and suppress tumorigenesis	cAMP	[^Citation63]

Figure 2 FTO overexpression in tumors and the regulation of some targets and signaling pathways.

Table 2 Mechanisms of Various Inhibitors by Inhibiting FTO-Mediated m6A Demethylation

Inhibitors	Mechanisms	The Mechanisms of Anti-Cancer Effect	References
Rhein	Rhein competitively binds to the active site of FTO and inhibits m6A demethylation	Rhein combine with nilotinib is a more effective treatment for leukemia in mice	[^Citation64]
MA/MA2	MA/MA2 selectively inhibits m6A demethylation of FTO	MA2 significantly inhibits the growth and self-renewal of glioblastoma (GSC) in vitro and prolongs the survival time of GSC mice	[^Citation38,Citation70]
FB23/FB23-2	FB23/FB23-2 directly binds to FTO and selectively inhibit FTO’s m6A demethylase activity	FB23-2 inhibits the proliferation of human acute myeloid leukemia (AML) cell lines and primary AML cells in vitro, and promotes cell differentiation/apoptosis	[^Citation66]
R-2HG	R-2HG inhibits the activity of FTO	R-2HG inhibits the progression of leukemia and glioblastoma by targeting the FTO/M6A/MYC/CEBPA signaling pathway	[^Citation67]
MO-I-500	MO-I-500 is a mimic of 2-OG, which can selectively inhibit FTO demethylation and increase intracellular m6A levels	MO-I-500 can significantly inhibit the growth of breast cancer cells in vivo and in vitro	[^Citation68,Citation69]

Huang Y, Su R, Sheng Y, et al. Small-molecule targeting of oncogenic FTO demethylase in acute myeloid leukemia. Cancer Cell. 2019;35(4):677–691.e610. doi:10.1016/j.ccell.2019.03.006

 PubMed Web of Science ®Google Scholar

Li Z, Weng H, Su R, et al. FTO plays an oncogenic role in acute myeloid leukemia as a N(6)-methyladenosine RNA demethylase. Cancer Cell. 2017;31(1):127–141. doi:10.1016/j.ccell.2016.11.017

 PubMed Web of Science ®Google Scholar

Liu Y, Wang R, Zhang L, Li J, Lou K, Shi B. The lipid metabolism gene FTO influences breast cancer cell energy metabolism via the PI3K/AKT signaling pathway. Oncol Lett. 2017;13(6):4685–4690. doi:10.3892/ol.2017.6038

 PubMed Web of Science ®Google Scholar

Niu Y, Lin Z, Wan A, et al. RNA N6-methyladenosine demethylase FTO promotes breast tumor progression through inhibiting BNIP3. Mol Cancer. 2019;18(1):46. doi:10.1186/s12943-019-1004-4

 PubMed Web of Science ®Google Scholar

Liu J, Ren D, Du Z, Wang H, Zhang H, Jin Y. m6A demethylase FTO facilitates tumor progression in lung squamous cell carcinoma by regulating MZF1 expression. Biochem Biophys Res Commun. 2018;502(4):456–464. doi:10.1016/j.bbrc.2018.05.175

 PubMed Web of Science ®Google Scholar

Li J, Han Y, Zhang H, et al. The m6A demethylase FTO promotes the growth of lung cancer cells by regulating the m6A level of USP7 mRNA. Biochem Biophys Res Commun. 2019;512(3):479–485. doi:10.1016/j.bbrc.2019.03.093

 PubMed Web of Science ®Google Scholar

Zou D, Dong L, Li C, Yin Z, Rao S, Zhou Q. The m6A eraser FTO facilitates proliferation and migration of human cervical cancer cells. Cancer Cell Int. 2019;19:321. doi:10.1186/s12935-019-1045-1

 PubMed Web of Science ®Google Scholar

Zhang Z, Zhou D, Lai Y, et al. Estrogen induces endometrial cancer cell proliferation and invasion by regulating the fat mass and obesity-associated gene via PI3K/AKT and MAPK signaling pathways. Cancer Lett. 2012;319(1):89–97. doi:10.1016/j.canlet.2011.12.033

 PubMed Web of Science ®Google Scholar

Cui Q, Shi H, Ye P, et al. mA RNA methylation regulates the self-renewal and tumorigenesis of glioblastoma stem cells. Cell Rep. 2017;18(11):2622–2634. doi:10.1016/j.celrep.2017.02.059

 PubMed Web of Science ®Google Scholar

Tang X, Liu S, Chen D, Zhao Z, Zhou J. The role of the fat mass and obesity-associated protein in the proliferation of pancreatic cancer cells. Oncol Lett. 2019;17(2):2473–2478. doi:10.3892/ol.2018.9873

 PubMed Web of Science ®Google Scholar

Su Y, Huang J, Hu J. mA RNA methylation regulators contribute to malignant progression and have clinical prognostic impact in gastric cancer. Front Oncol. 2019;9:1038. doi:10.3389/fonc.2019.01038

 PubMed Web of Science ®Google Scholar

Li J, Zhu L, Shi Y, Liu J, Lin L, Chen X. m6A demethylase FTO promotes hepatocellular carcinoma tumorigenesis via mediating PKM2 demethylation. Am J Transl Res. 2019;11(9):6084–6092.

 PubMed Web of Science ®Google Scholar

Mittenbühler MJ, Saedler K, Nolte H, et al. Hepatic FTO is dispensable for the regulation of metabolism but counteracts HCC development in vivo. Mol Metabol. 2020;42:101085. doi:10.1016/j.molmet.2020.101085

 PubMed Web of Science ®Google Scholar

Zhao Y, You S, Yu YQ, et al. Decreased nuclear expression of FTO in human primary hepatocellular carcinoma is associated with poor prognosis. Int J Clin Exp Pathol. 2019;12(9):3376–3383.

 PubMed Web of Science ®Google Scholar

Zhuang C, Zhuang C, Luo X, et al. N6-methyladenosine demethylase FTO suppresses clear cell renal cell carcinoma through a novel FTO-PGC-1α signalling axis. J Cell Mol Med. 2019;23(3):2163–2173. doi:10.1111/jcmm.14128

 PubMed Web of Science ®Google Scholar

Huang H, Wang Y, Kandpal M, et al. FTO-dependent N (6)-methyladenosine modifications inhibit ovarian cancer stem cell self-renewal by blocking cAMP signaling. Cancer Res. 2020;80(16):3200–3214. doi:10.1158/0008-5472.Can-19-4044

 PubMed Web of Science ®Google Scholar

Chen B, Ye F, Yu L, et al. Development of cell-active N6-methyladenosine RNA demethylase FTO inhibitor. J Am Chem Soc. 2012;134(43):17963–17971. doi:10.1021/ja3064149

 PubMed Web of Science ®Google Scholar

Huang Y, Yan J, Li Q, et al. Meclofenamic acid selectively inhibits FTO demethylation of m6A over ALKBH5. Nucleic Acids Res. 2015;43(1):373–384. doi:10.1093/nar/gku1276

 PubMed Web of Science ®Google Scholar

Su R, Dong L, Li C, et al. R-2HG exhibits anti-tumor activity by targeting FTO/m(6)A/MYC/CEBPA signaling. Cell. 2018;172(1–2):90–105.e123. doi:10.1016/j.cell.2017.11.031

 PubMed Web of Science ®Google Scholar

Zheng G, Cox T, Tribbey L, et al. Synthesis of a FTO inhibitor with anticonvulsant activity. ACS Chem Neurosci. 2014;5(8):658–665. doi:10.1021/cn500042t

 PubMed Web of Science ®Google Scholar

Singh B, Kinne HE, Milligan RD, Washburn LJ, Olsen M, Lucci A. Important role of FTO in the survival of rare panresistant triple-negative inflammatory breast cancer cells facing a severe metabolic challenge. PLoS One. 2016;11(7):e0159072. doi:10.1371/journal.pone.0159072

 PubMed Web of Science ®Google Scholar