Lin Sang, Tan Sheng, Peng Yonglin, Tulamaiti Aziguli, Du Wenfei, Ding Keshuo, Chen Changyu, Wu Jun, Li Hua, Xu Wei, Sun Jielin, Zhang Xue-Li, Zhang Zhi-Gang, Zhao Xiaodong
Shanghai Center for Systems Biomedicine, Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China.
State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Nat Commun. 2025 Jul 1;16(1):5947. doi: 10.1038/s41467-025-61197-z.
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.
神经递质5-羟色胺（5-HT）在神经生物学和肿瘤学中均发挥着并行作用。除了受体介导的信号转导模式外，5-羟色胺还可共价整合到组蛋白中（这种翻译后修饰称为组蛋白5-羟色胺化），并作为与基因表达许可相关的表观遗传标记。然而，组蛋白5-羟色胺化如何影响肿瘤发生尚不清楚。在本研究中，我们观察到与正常组织和细胞系相比，胰腺导管腺癌（PDAC）组织和细胞系中组蛋白5-羟色胺化（H3K4me3Q5ser）和转谷氨酰胺酶2（TGM2，催化5-羟色胺化的酶）水平更高，并且抑制组蛋白5-羟色胺化可抑制PDAC的发展。机制上，我们证明TGM2介导的编码硬脂酰辅酶A去饱和酶（SCD）基因启动子处的组蛋白5-羟色胺化上调其表达，并通过脂质代谢重塑驱动PDAC发展。总体而言，本研究揭示组蛋白5-羟色胺化是PDAC肿瘤发生的重要驱动因素。
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