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<p>N6-methyladenosine (m<sup>6</sup>A) modification has emerged as a common chemical modification in epigenetic regulation. However, whether this m<sup>6</sup>A modification is involved in glycolysis metabolism in pancreatic ductal adenocarcinoma (PDAC) remains elusive. Multiomics integration strategies, including metabolomics, m<sup>6</sup>A-seq and transcriptome sequencing, were utilized to evaluate the associations between m<sup>6</sup>A modifications and key processes of glucose metabolism in PDAC. Spontaneous PDAC mice (LSLKras<sup>G12D/+</sup>, LSL-Trp53<sup>R172H/+</sup>, Pdx1-Cre; KPC) with FTO-conditional knockout and organoids were used to evaluate the effects of FTO stimulation on PDAC cell glycolysis and tumorigenesis. Series of in vivo and vitro functional analysis revealed that FTO promoted migratory capacity and glycolysis of PDAC cells. Mechanistically, FTO elevates the mRNA expression of the transcription factor C-Jun in a m<sup>6</sup>A-YTHDF2-dependent manner and further transcriptionally upregulates PFKM expression. Translational studies involving organoid models and xenograft tumor models revealed that the use of FTO inhibitors significantly suppressed PDAC growth. Our findings uncover that targeting the m<sup>6</sup>A-dependent FTO/C-Jun/PFKM glycolysis regulatory axis may be essential for the prevention and treatment of PDAC.</p>

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m6A demethylase FTO drives pancreatic ductal adenocarcinoma tumorigenesis and metastasis through remodeling PFKM mediated glycolysis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月3日

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  • Zhen Tan,
  • Jianhui Yang,
  • Yueyue Chen,
  • Heng Zhu,
  • Xiaomeng Liu,
  • He Xu,
  • Qingcai Meng,
  • Mingming Xiao,
  • Rong Tang,
  • Zeyin Rong,
  • Xianjun Yu,
  • Chen Liang,
  • Jin Xu

摘要

N6-methyladenosine (m6A) modification has emerged as a common chemical modification in epigenetic regulation. However, whether this m6A modification is involved in glycolysis metabolism in pancreatic ductal adenocarcinoma (PDAC) remains elusive. Multiomics integration strategies, including metabolomics, m6A-seq and transcriptome sequencing, were utilized to evaluate the associations between m6A modifications and key processes of glucose metabolism in PDAC. Spontaneous PDAC mice (LSLKrasG12D/+, LSL-Trp53R172H/+, Pdx1-Cre; KPC) with FTO-conditional knockout and organoids were used to evaluate the effects of FTO stimulation on PDAC cell glycolysis and tumorigenesis. Series of in vivo and vitro functional analysis revealed that FTO promoted migratory capacity and glycolysis of PDAC cells. Mechanistically, FTO elevates the mRNA expression of the transcription factor C-Jun in a m6A-YTHDF2-dependent manner and further transcriptionally upregulates PFKM expression. Translational studies involving organoid models and xenograft tumor models revealed that the use of FTO inhibitors significantly suppressed PDAC growth. Our findings uncover that targeting the m6A-dependent FTO/C-Jun/PFKM glycolysis regulatory axis may be essential for the prevention and treatment of PDAC.