ArticleJournal of experimental & clinical cancer research : CR2023
m6A eraser FTO impairs gemcitabine resistance in pancreatic cancer through influencing NEDD4 mRNA stability by regulating the PTEN/PI3K/AKT pathway.
Article in Journal of experimental & clinical cancer research : CR, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 62 papers, 1 of them a synthesis that pooled it.
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Who cites it
62 citing papers in PubMed, 1 synthesis or guideline pooled it, 79 citations in OpenAlex.
- Global research trends in mFrontiers in genetics · 2026Pooled it
- FTO-mediated mRNA biology · 2026Article
- The role, regulatory mechanisms, and therapeutic implications of FTO in gastrointestinal cancer.Genes & diseases · 2026Review
- It takes two to tango: the intersection of deubiquitinases and mMolecular cancer · 2026Review
- Hepatic Lipid Stress Drives Metabolic Dysfunction-Associated Steatohepatitis Progression through FTO O-GlcNAcylation-Induced m6A Demethylation of HRAS.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- ALKBH5 in Cancer-Associated Fibroblasts Governs an Epitranscriptomic Axis That Drives Pancreatic Cancer Metastasis.Cancer research · 2026Article
- DNMT1 Regulates Testosterone Synthesis in Aged Rat Leydig Cells via FTO-Mediated HSP90AA1 mAging cell · 2026Article
- PI3K/AKT signaling pathway: molecular crossroads in tumorigenesis and therapeutic innovation.Signal transduction and targeted therapy · 2026Review
- Ferroptosis Suppression by the MAdvanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Short-term methionine starvation induces de novo diurnal oscillations of hepatic m6A RNA methylation.bioRxiv : the preprint server for biology · 2026Article
- Fat Mass and Obesity-Associated Protein Contributes to Tumorigenesis and Drug Resistance of Diffuse Large B-Cell Lymphoma by Suppressing N6-Methyladenosine Methylation of Myc.The Kaohsiung journal of medical sciences · 2026Article
- Ubiquitination and NOncology letters · 2026Review
- The OAS1-FASN axis promotes pancreatic cancer by coordinating lipogenic stress and the unfolded protein response.Cell death & disease · 2026Article
- GPSM2 Promotes Pancreatic Cancer Progression Through METTL3-Mediated m6A Modification of YAP1 mRNA.Journal of cellular and molecular medicine · 2026Article
- Age- and Treatment-Specific TP53 and PI3K Alterations in Pancreatic Ductal Adenocarcinoma (PDAC) Revealed by Conversational Artificial Intelligence.International journal of molecular sciences · 2026Article
- Interplay of RNA mFASEB bioAdvances · 2026Article
- YTHDF2 in inflammation: Mechanisms and therapeutic strategies.Genes & diseases · 2026Review
- The RNA methylation modification as an immunometabolic regulatory hub in pancreatic cancer: from mechanistic insights to clinical translation perspectives.Molecular cancer · 2026Review
- CDC6/THBS1 accelerates pancreatic cancer progression via AKT-mediated glycolytic reprogramming.Cell death & disease · 2026Article
- Filgotinib inhibits METTL3-mediated mNPJ precision oncology · 2026Article
2 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 2 countries.
Funding
Abstract
backgroundGemcitabine resistance has brought great challenges to the treatment of pancreatic cancer. The N6-methyladenosine (m6A) mutation has been shown to have a significant regulatory role in chemosensitivity; however, it is not apparent whether gemcitabine resistance can be regulated by fat mass and obesity-associated protein (FTO).
methodsCells with established gemcitabine resistance and tissues from pancreatic cancer patients were used to evaluate FTO expression. The biological mechanisms of the effects of FTO on gemcitabine resistant cells were investigated using CCK-8, colony formation assay, flow cytometry, and inhibitory concentration 50. Immunoprecipitation/mass spectrometry, MeRIP-seq, RNA sequencing and RIP assays, RNA stability, luciferase reporter, and RNA pull down assays were employed to examine the mechanism of FTO affecting gemcitabine resistant pancreatic cancer cells.
resultsThe results revealed that FTO was substantially expressed in cells and tissues that were resistant to gemcitabine. Functionally, the gemcitabine resistance of pancreatic cancer could be enhanced by FTO, while its depletion inhibited the growth of gemcitabine resistant tumor cells in vivo. Immunoprecipitation/mass spectrometry showed that the FTO protein can be bound to USP7 and deubiquitinated by USP7, leading to the upregulation of FTO. At the same time, FTO knockdown significantly decreased the expression level of NEDD4 in an m6A-dependent manner. RNA pull down and RNA immunoprecipitation verified YTHDF2 as the reader of NEDD4, which promoted the chemoresistance of gemcitabine resistant cells. FTO knockdown markedly increased the PTEN expression level in an NEDD4-dependent manner and influenced the chemosensitivity to gemcitabine through the PI3K/AKT pathway in pancreatic cancer cells.
conclusionIn conclusion, we found that gemcitabine resistance in pancreatic cancer can be influenced by FTO that demethylates NEDD4 RNA in a m6A-dependent manner, which then influences the PTEN expression level and thereby affects the PI3K/AKT pathway. We also identified that the FTO level can be upregulated by USP7.
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Registered trials
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