Professor Xiaodong Zhao's team from Shanghai Center for Systems Biomedicine at Shanghai Jiao Tong University, together with collaborators, recently published a research paper entitled "Histone serotonylation promotes pancreatic cancer development via lipid metabolism remodeling" in Nature Communications. This study reveals the role of histone serotonylation modification in pancreatic cancer progression, demonstrating that this modification promotes pancreatic cancer progression by remodeling lipid metabolism. These findings provide a potential target for developing new diagnostic and treatment strategies for pancreatic cancer.

Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter that functions in the central nervous system and is associated with mood, sleep, and cognition. Over the past decade, numerous studies have also revealed that 5-HT influences tumor progression. By binding to specific membrane receptors and coupling with diverse signaling pathways, 5-HT promotes development of cancers such as lung cancer, breast cancer, and colorectal cancer. Beyond receptor interactions, 5-HT can also serve as a substrate for covalent post-translational modifications of proteins. The glutamine residue at position 5 of histone H3 can undergo serotonylation modification (H3K4me3Q5ser), a permissive epigenetic modification. The flexible tail domains of histones harbor multiple amino acid residues that can form various post-translational modifications, playing crucial roles in cancer initiation, progression, and treatment. However, how histone serotonylation affects tumor progression remains poorly understood.

Pancreatic ductal adenocarcinoma (PDAC) is one most deadly malignancies, with an overall 5-year survival rate below 10%. Current therapies show limited efficacy for PDAC patients, underscoring the urgent need to further understand the molecular mechanisms governing PDAC development. Our collaborators ever demonstrated that the 5-HT signaling pathway promotes malignant progression of pancreatic cancer by enhancing aerobic glycolysis in cancer cells. This raises the question whether histone serotonylation modification contributes to pancreatic cancer progression?

Through analysis of clinical samples from pancreatic cancer patients, this study revealed that H3K4me3Q5ser and transglutaminase 2 (TGM2) — the enzyme catalyzing histone H3 serotonylation — are highly expressed in pancreatic cancer and correlate with poor patient prognosis. In pancreatic cancer cells, either TGM2 knockdown or overexpression of H3.3Q5A mutation (the mutation attenuating H3K4me3Q5ser modification) significantly suppresses the proliferation and colony formation of PDAC cells, and increases cellular apoptosis. Moreover, in vivo tumor formation experiments in mice demonstrated that suppressing H3K4me3Q5ser modification levels markedly inhibits tumor growth. Mechanistically, elevated 5-HT levels in pancreatic cancer cells induce TGM2-mediated histone serotonylation at the promoter region of the gene encoding stearoyl-CoA desaturase (SCD) up-regulates its expression and drives PDAC progression by lipid metabolism remodeling.

Collectively, this study reveals that histone serotonylation modification serves as a critical driver of pancreatic cancer progression by upregulating SCD and remodeling lipid metabolism. The discovery provides a foundation for exploring potential therapeutic strategies against PDAC.

Prof. Xiaodong Zhao from Shanghai Center for Systems Biomedicine and Prof. Zhi-gang Zhang from the Shanghai Cancer Institute, Ren Ji Hospital serve as co-corresponding authors of this article. Sang Lin (PhD student) from Prof. Xiaodong Zhao’s team and associate Prof. Sheng Tan are co-first authors. This work was supported by the National Natural Science Foundation of China (NSFC) and the National Key Research and Development Program of China.

Paper Link：https://www.nature.com/articles/s41467-025-61197-z#Sec1