FTO m6A Demethylase in Obesity and Cancer: Implications and Underlying Molecular Mechanisms

Abstract

Fat mass and obesity-associated protein (FTO) is the first reported RNA N6-methyladenosine (m6A) demethylase in eukaryotic cells. m6A is considered as the most abundant mRNA internal modification, which modulates several cellular processes including alternative splicing, stability, and expression. Genome-wide association studies (GWAS) identified single-nucleotide polymorphisms (SNPs) within FTO to be associated with obesity, as well as cancer including endometrial cancer, breast cancer, pancreatic cancer, and melanoma. Since the initial classification of FTO as an m6A demethylase, various studies started to unravel a connection between FTO's demethylase activity and the susceptibility to obesity on the molecular level. FTO was found to facilitate adipogenesis, by regulating adipogenic pathways and inducing pre-adipocyte differentiation. FTO has also been investigated in tumorigenesis, where emerging studies suggest m6A and FTO levels are dysregulated in various cancers, including acute myeloid leukemia (AML), glioblastoma, cervical squamous cell carcinoma (CSCC), breast cancer, and melanoma. Here we review the molecular bases of m6A in tumorigenesis and adipogenesis while highlighting the controversial role of FTO in obesity. We provide recent findings confirming FTO's causative link to obesity and discuss novel approaches using RNA demethylase inhibitors as targeted oncotherapies. Our review aims to confirm m6A demethylation as a risk factor in obesity and provoke new research in FTO and human disorders.

Keywords: N6-methyladenosine (m6A); adipogenesis; cancer; fat mass and obesity-associated (FTO) protein; obesity; tumorigenesis.

Figure 1

FTO molecular mechanisms in association with adipogenic pathways. (A) Inverse correlation between FTO overexpression and lipid accumulation as reported in porcine adipocytes. (B) Overexpression of FTO in human subjects homozygous for FTO SNP rs9939609 risk allele, resulting in increased levels of the hunger hormone ghrelin. (C) m6A and alternative splicing regulation: perturbed binding of SRSF2 to RUNX1T1 results in the skipping exon 6 and generating the pro-adipogenic RUNX1T1 S variant. (D) Mechanistically, RUNX1T1 S-isoform promotes adipogenic differentiation via increasing D-type Cyclin genes (Cyclin D1 & D3) during the MCE phase. (E) FTO regulatory role in skeletal muscle cells’ lipid accumulation capacity: AMPK activation downregulates FTO, resulting in reduced lipid accumulation. (F) FTO regulatory role in adipocyte cell cycle progression: FTO inhibition results in m6A hyper-methylation of two mitotic regulators’ transcripts CCNA2 and CDK2, which are recognized and degraded by YTHDF2 m6A reader; impairing cell cycle and suppressing adipogenesis. (G) Zfp217 interaction with FTO promotes adipogenesis via transcriptional and post-transcriptional regulatory mechanisms. (H) Association between metabolism and RNA m6A demethylation: NADP binding to FTO enhances its activity and promotes adipogenesis. (I) Connecting m6A role in adipogenesis with autophagy: FTO reduces m6A levels on two autophagy-related genes ATG5 and ATG7, stabilizing them from decay by YTHDF2; thus promoting autophagy and adipogenesis. (J) FTO promotes thermogenesis and white-to-beige fat transition: FTO knockdown produces m6A hyper-methylated HIF1A and increases its translation through a YTHDC2-mediated process; HIF1A, in turn, activates thermogenic genes PGC1A, PRDM16, and PPARG, which promote white adipocyte “browning”, as an anti-obesity approach. Abbreviations: RUNX1T1: Runt-related transcription factor 1; SRSF2: splicing regulatory protein; MCE: mitotic clonal expansion phase; AMPK: AMP-activated protein kinase; CCNA2: cyclin A2; CDK2: cyclin-dependent kinase 2; Zfp217: Zinc finger protein 217; NADP: nicotinamide adenine dinucleotide phosphate; ATG5: autophagy-related gene 5; ATG7: autophagy-related gene 7; HIF1A: hypoxia inducible factor 1 subunit alpha.

Figure 2

FTO upregulation in various human cancers and its molecular implications as an m6A demethylase, indicated by the regulation of different targets and affected signaling pathways. (A) FTO upregulation in AML modulates ASB2/RARA levels, hence, promoting AML cellular viability and proliferation. FTO inhibition via FB23-2 inhibits AML progression, by upregulating ASB2/RARA and downregulating MYC/CEBPA. (B) Given FTO’s tumorigenic role in glioblastoma, its inhibition via MA2 suppresses GSCs self-renewal and tumorigenesis. Additionally, inhibiting FTO using R-2HG exerts anti-tumor functions in lethal glioma and leukemia by modulating MYC/CEBPA levels. (C) FTO upregulation in CSCC induces chemo-radiotherapy resistance by increasing β-catenin and activating the ERCC1 pathway. E2F1/MYC are also upregulated targets in CSCC that promote oncogenic functions. (D) FTO overexpression in lung cancer upregulates MZF1 and USP7 levels via modulating their m6A levels. Thus, promoting lung cancer cells’ proliferation, invasion, and colony formation, while inhibiting their apoptosis. (E) In breast cancer cells, FTO upregulation demethylates BNIP3 as a downstream target and downregulates it in a YTHDF2-independent manner, and promoting oncogenic roles like metastasis. (F) In melanoma, upregulated FTO and reduced m6A levels, stabilize melanoma-promoting genes namely, PDCD1, CXCR4, and SOX10 in a YTHDF2-mediated process. Consequently, increasing melanoma migration, proliferation, and immunotherapy resistance. (G) In endometrial carcinoma, higher HOXB13 expression activates Wnt signaling and promotes metastasis. (H) In pancreatic cancer, FTO overexpression leads to upregulating c-MYC oncogene and enhancing pancreatic cancer proliferation. FTO’s additional role as a tumor suppressor in pancreatic cancer is discussed in the text. Abbreviations: ASB2: Ankyrin repeat and SOCS box protein 2; RARA: retinoic acid receptor α; GSCs: glioblastoma stem cells; MA: Meclofenamic acid; R-2HG: R-2-hydroxyglutarate; ERCC1: excision repair cross-complementation group 1; MZF1: Myeloid Zinc Finger Protein 1; USP7: ubiquitin-specific protease-7; BNIP3: BCL2 Interacting Protein 3; HOXB13: homeobox transcription factor.