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Histone serotonylation promotes pancreatic cancer development via lipid metabolism remodeling

Author

Listed:
  • Sang Lin

    (Shanghai Jiao Tong University)

  • Sheng Tan

    (Shanghai Jiao Tong University)

  • Yonglin Peng

    (Shanghai Jiao Tong University)

  • Aziguli Tulamaiti

    (Shanghai Jiao Tong University)

  • Wenfei Du

    (Shanghai Jiao Tong University)

  • Keshuo Ding

    (Anhui Medical University)

  • Changyu Chen

    (The First Affiliated Hospital of Anhui Medical University)

  • Jun Wu

    (East China Normal University)

  • Hua Li

    (Shanghai Jiao Tong University
    Suzhou Vocational Health College)

  • Wei Xu

    (Shanghai Jiao Tong University School of Medicine)

  • Jielin Sun

    (Shanghai Jiao Tong University)

  • Xue-Li Zhang

    (Shanghai Jiao Tong University)

  • Zhi-gang Zhang

    (Shanghai Jiao Tong University)

  • Xiaodong Zhao

    (Shanghai Jiao Tong University)

Abstract

Neurotransmitter serotonin (5-hydroxytryptamine [5-HT]) has emerged to play parallel roles in both neurobiology and oncology. Apart from receptor-mediated signaling transduction pattern, serotonin can be covalently integrated into histone (the post-translational modification known as histone serotonylation) and serve as an epigenetic mark associated with permissive gene expression. However, how histone serotonylation influences tumorigenesis is yet to be understood. In this study, we observe the higher levels of histone serotonylation (H3K4me3Q5ser) and transglutaminases 2 (TGM2, the enzyme catalyzing serotonylation) in both pancreatic ductal adenocarcinoma (PDAC) tissues and cell lines in comparison with their normal counterparts, and inhibition of histone serotonylation suppresses PDAC development. Mechanistically, we demonstrate that TGM2-mediated histone serotonylation at promoter of the gene encoding stearoyl-CoA desaturase (SCD) up-regulates its expression and drives PDAC development by lipid metabolism remodeling. Collectively, this study reveals histone serotonylation as an important driver of PDAC tumorigenesis.

Suggested Citation

  • Sang Lin & Sheng Tan & Yonglin Peng & Aziguli Tulamaiti & Wenfei Du & Keshuo Ding & Changyu Chen & Jun Wu & Hua Li & Wei Xu & Jielin Sun & Xue-Li Zhang & Zhi-gang Zhang & Xiaodong Zhao, 2025. "Histone serotonylation promotes pancreatic cancer development via lipid metabolism remodeling," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-61197-z
    DOI: 10.1038/s41467-025-61197-z
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