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, Xueli Zhang, Zhigang Zhang, Xiaodong Zhao
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. The neurotransmitter serotonin regulates cancer through receptor-signaling activation, but also epigenetics mechanisms by serotonylation. Here, the authors show that histone serotonylation promotes pancreatic cancer progression by upregulating stearoyl-CoA desaturase (SCD), which remodels lipid metabolism, suggesting a potential target for therapy.