Histone serotonylation promotes pancreatic cancer development via lipid metabolism remodeling
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 () and
Xiaodong Zhao ()
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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
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
Nature Communications, 2025, vol. 16, issue 1, 1-14
Abstract:
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.
Date: 2025
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DOI: 10.1038/s41467-025-61197-z
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