Biomarker: FTO

Histology type: endometrial carcinoma

Country: China

Region: Nanjing

Followed up time :

Conclusion: We found that the expression of FTO can promote the metastasis of EC. Mechanistically, FTO removed the m6A modification from HOXB13 mRNA and abolished the YTHDF2-mediated degradation of HOXB13, promoting HOXB13 protein expression and activates the WNT signalling pathway, and promotes EC invasion and metastasis

Sample type : tissue

Sample method: immunohistochemistry

Expression pattern : FTO demethylates m6A modifications

Expression elevation: IHC staining was semi-quantitatively evaluated based on stain intensity and the percentage of positive cells. Stain intensities were categorized as 0 (negative), 1 (weakly positive), 2 (moderately positive), or 3 (strongly positive). The percentage of positive cells were categorized as 1 (0%–10%), 2 (11%–50%), 3 (51%–80%), or 4 (81%–100%). The final score for each section was determined by multiplying the staining intensity score by the percentage staining score.

Funtion Uniprot: RNA demethylase that mediates oxidative demethylation of different RNA species, such as mRNAs, tRNAs and snRNAs, and acts as a regulator of fat mass, adipogenesis and energy homeostasis (PubMed:22002720, PubMed:26458103, PubMed:28002401, PubMed:30197295, PubMed:26457839, PubMed:25452335). Specifically demethylates N6-methyladenosine (m6A) RNA, the most prevalent internal modification of messenger RNA (mRNA) in higher eukaryotes (PubMed:22002720, PubMed:26458103, PubMed:30197295, PubMed:26457839, PubMed:25452335). M6A demethylation by FTO affects mRNA expression and stability (PubMed:30197295). Also able to demethylate m6A in U6 small nuclear RNA (snRNA) (PubMed:30197295). Mediates demethylation of N6,2'-O-dimethyladenosine cap (m6A(m)), by demethylating the N6-methyladenosine at the second transcribed position of mRNAs and U6 snRNA (PubMed:28002401, PubMed:30197295). Demethylation of m6A(m) in the 5'-cap by FTO affects mRNA stability by promoting susceptibility to decapping (PubMed:28002401). Also acts as a tRNA demethylase by removing N1-methyladenine from various tRNAs (PubMed:30197295). Has no activity towards 1-methylguanine (PubMed:20376003). Has no detectable activity towards double-stranded DNA (PubMed:20376003). Also able to repair alkylated DNA and RNA by oxidative demethylation: demethylates single-stranded RNA containing 3-methyluracil, single-stranded DNA containing 3-methylthymine and has low demethylase activity towards single-stranded DNA containing 1-methyladenine or 3-methylcytosine (PubMed:18775698, PubMed:20376003). Ability to repair alkylated DNA and RNA is however unsure in vivo (PubMed:18775698, PubMed:20376003). Involved in the regulation of fat mass, adipogenesis and body weight, thereby contributing to the regulation of body size and body fat accumulation (PubMed:18775698, PubMed:20376003). Involved in the regulation of thermogenesis and the control of adipocyte differentiation into brown or white fat cells (PubMed:26287746). Regulates activity of the dopaminergic midbrain circuitry via its ability to demethylate m6A in mRNAs (By similarity). Plays an oncogenic role in a number of acute myeloid leukemias by enhancing leukemic oncogene-mediated cell transformation: acts by mediating m6A demethylation of target transcripts such as MYC, CEBPA, ASB2 and RARA, leading to promote their expression (PubMed:28017614, PubMed:29249359).

UniProt ID: Q9C0B1

UniProt Link: https://www.uniprot.org/uniprotkb/Q9C0B1/entry

Molecular function from UniProt:

Tissue specificity from UniProt: Ubiquitously expressed, with relatively high expression in adrenal glands and brain; especially in hypothalamus and pituitary (PubMed:17434869, PubMed:17496892). Highly expressed in highly expressed in acute myeloid leukemias (AML) with t(11;11)(q23;23) with KMT2A/MLL1 rearrangements, t(15;17)(q21;q21)/PML-RARA, FLT3-ITD, and/or NPM1 mutations (PubMed:28017614).

Subcellular UniProt: #Cytoplasm #Nucleus

Alternative name from UniProt:

Caution: According to a report, mainly mediates demethylation of N6,2'-O-dimethyladenosine cap (m6A(m)), by demethylating the N6-methyladenosine adjacent to mRNA cap, whereas it has low activity toward internal N6-methyladenosine (m6A) in mRNAs (PubMed:28002401). According to a second report, has strong activity toward internal N6-methyladenosine (m6A) in mRNAs and is able to demethylate different RNA species, such as tRNA, mRNA or small nuclear RNA (snRNA), depending on the context and subcellular location (PubMed:30197295)

Catalytic activity: 2-oxoglutarate + a 5'-end (N7-methyl 5'-triphosphoguanosine)-(N6,2'-O-dimethyladenosine) in mRNA + O2 = a 5'-end (N7-methyl 5'-triphosphoguanosine)-(2'-O-methyladenosine) in mRNA + CO2 + formaldehyde + succinate; 2-oxoglutarate + an N6-methyladenosine in mRNA + O2 = an adenosine in mRNA + CO2 + formaldehyde + succinate ;2-oxoglutarate + N6-methyladenosine in U6 snRNA + O2 = adenosine in U6 snRNA + CO2 + formaldehyde + succinate ;2-oxoglutarate + a 5'-end (N7-methyl 5'-triphosphoguanosine)-(N6,2'-O-dimethyladenosine) in U6 snRNA + O2 = a 5'-end (N7-methyl 5'-triphosphoguanosine)-(2'-O-methyladenosine) in U6 snRNA + CO2 + formaldehyde + succinate ;2-oxoglutarate + an N1-methyladenosine in tRNA + O2 = an adenosine in tRNA + CO2 + formaldehyde + succinate ;

Activity regulation: Activated by ascorbate (By similarity). Inhibited by N-oxalylglycine, fumarate and succinate (By similarity). RNA N6-methyladenosine demethylase activity is inhibited by fluorescein derivatives (PubMed:26457839). RNA N6-methyladenosine demethylase activity is selectively inhibited by meclofenamic acid; inhibition is specific to FTO and meclofenamic acid does not inhibit ALKBH5 (PubMed:25452335). Specifically inhibited by R-2-hydroxyglutarate (R-2HG), an oncometabolite that also exerts a broad antileukemic activity (PubMed:29249359). Inhibition by R-2HG leads to increased level of N6-methyladenosine-containing transcripts, leading to down-regulate expression of MYC and CEBPA transcripts (PubMed:29249359).

Recommended name: Alpha-ketoglutarate-dependent dioxygenase FTO

Gene name from HGNC: FTO (ALKBH9, KIAA1752, MGC5149)

HPA class: Disease related genes Enzymes Human disease related genes Potential drug targets

AlphaFold DB: Q9C0B1

AlphaFold Link: https://alphafold.ebi.ac.uk/entry/Q9C0B1

HPA link: https://www.proteinatlas.org/ENSG00000140718-FTO

Tissue specificity RNA from HPA: Low tissue specificity

Tissue expression from HPA: General nuclear expression.

Single cell type specificity Cell type enhanced (Oligodendrocytes, Inhibitory neurons, Excitatory neurons, Oligodendrocyte precursor cells, Respiratory ciliated cells, Astrocytes)

Immune cell specificity: Low immune cell specificity

Subcellular summary HPA Located in Vesicles, Cytosol (Single cell variability)

Cancer prognostic summary HPA Gene product is not prognostic

Pathology link: https://www.proteinatlas.org/ENSG00000140718-FTO/pathology

Pathology endo: https://www.proteinatlas.org/ENSG00000140718-FTO/pathology/endometrial+cancer

Phenotype ID: 612938;601665;

Disease: Growth retardation, developmental delay, and facial dysmorphism (GDFD);Obesity (OBESITY);

Note1: The disease is caused by variants affecting the gene represented in this entry;Disease susceptibility is associated with variants affecting the gene represented in this entry. It is unclear whether variations associated with obesity directly affect FTO function or alter the expression of adjacent genes such as IRX3, rather than FTO itself (PubMed:24646999, PubMed:26287746). A pathogenic intronic FTO variation (rs1421085) disrupts an evolutionarily conserved motif for ARID5B binding (PubMed:26287746). Loss of ARID5B binding results in overexpression of two genes distal to FTO, IRX3 and IRX5. IRX3 and IRX5 overexpression shifts pre-adipocytes differentiation from brown to white fat cells, resulting in increased lipid storage and loss of mitochondrial thermogenesis (PubMed:26287746);

OMIM: 610966

OMIM link1: https://www.omim.org/entry/612938;https://www.omim.org/entry/601665;

OMIM link2: https://www.omim.org/entry/610966

HGNC ID: HGNC:24678

HGNC link: https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:24678