5-HT orchestrates histone serotonylation and citrullination to drive neutrophil extracellular traps and liver metastasis
Kaiyuan Liu, Yingchao Zhang, Genyu Du, Xinyu Chen, Lingling Xiao, Luyao Jiang, Na Jing, Penghui Xu, Chaoxian Zhao, Yiyun Liu, Huifang Zhao, Yujiao Sun, Jinming Wang, Chaping Cheng, Deng Wang, Jiahua Pan, Wei Xue, Pengcheng Zhang, Zhi-Gang Zhang, Wei-Qiang Gao, Shu-Heng Jiang, Kai Zhang, Helen He Zhu
Kaiyuan Liu, Yingchao Zhang, Genyu Du, Xinyu Chen, Lingling Xiao, Luyao Jiang, Na Jing, Penghui Xu, Chaoxian Zhao, Yiyun Liu, Huifang Zhao, Yujiao Sun, Jinming Wang, Chaping Cheng, Deng Wang, Jiahua Pan, Wei Xue, Pengcheng Zhang, Zhi-Gang Zhang, Wei-Qiang Gao, Shu-Heng Jiang, Kai Zhang, Helen He Zhu
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Research Article Cell biology Oncology

5-HT orchestrates histone serotonylation and citrullination to drive neutrophil extracellular traps and liver metastasis

Abstract

Serotonin (5-HT) is a neurotransmitter that has been linked to tumorigenesis. Whether and how 5-HT modulates cells in the microenvironment to regulate tumor metastasis is largely unknown. Here, we demonstrate that 5-HT was secreted by neuroendocrine prostate cancer (NEPC) cells to communicate with neutrophils and to induce the formation of neutrophil extracellular traps (NETs) in the liver, which in turn facilitated the recruitment of disseminated cancer cells and promoted liver metastasis. 5-HT induced histone serotonylation (H3Q5ser) and orchestrated histone citrullination (H3cit) in neutrophils to trigger chromatin decondensation and facilitate the formation of NETs. Interestingly, we uncovered in this process a reciprocally reinforcing effect between H3Q5ser and H3cit and a crosstalk between the respective writers enzyme transglutaminase 2 (TGM2) and peptidylarginine deiminase 4 (PAD4). Genetic ablation or pharmacological targeting of TGM2, or inhibition of the 5-HT transporter (SERT) with the FDA-approved antidepressant drug fluoxetine reduced H3Q5ser and H3cit modifications, suppressed NET formation, and effectively inhibited NEPC, small-cell lung cancer, and thyroid medullary cancer liver metastasis. Collectively, the 5-HT–triggered production of NETs highlights a targetable neurotransmitter/immune axis that drives liver metastasis of NE cancers.

Authors

Kaiyuan Liu, Yingchao Zhang, Genyu Du, Xinyu Chen, Lingling Xiao, Luyao Jiang, Na Jing, Penghui Xu, Chaoxian Zhao, Yiyun Liu, Huifang Zhao, Yujiao Sun, Jinming Wang, Chaping Cheng, Deng Wang, Jiahua Pan, Wei Xue, Pengcheng Zhang, Zhi-Gang Zhang, Wei-Qiang Gao, Shu-Heng Jiang, Kai Zhang, Helen He Zhu

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Figure 7

H3Q5ser and H3cit are mutually enhanced and share chromatin occupancy on a genome-wide scale.

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H3Q5ser and H3cit are mutually enhanced and share chromatin occupancy on...
(A) Immunoblotting assay demonstrates that the H3.3(Q5A) mutant leads to deficient H3Q5ser modification and a reduced H3cit level. (B) Immunoblotting data show that either H3.3(R2A), H3.3(R8A), H3.3(R17A) mutants alone or in combination H3.3(R2,8,17A) result in deficient H3cit modification and a repressed H3Q5ser level. (C and D) Mutant H3.3(Q5A) (C) or H3.3(R2,8,17A) (D) attenuates the recruitment of each other’s epigenetic writer, as exemplified by deficient binding of either PAD4 (C) or TGM2 (D) to histone H3. (E and F) In vitro catalytic assay showing that H3Q5ser-modified peptides enhanced PAD4-mediated H3cit compared with the unmodified H3 peptide control. (G and H) In vitro catalytic assay revealing that H3cit-modified peptides promoted TGM2-mediated H3Q5ser compared with the unmodified H3 peptide control. (I) Venn diagrams show the overlapped H3cit and H3Q5ser peaks in HL-60 granulocytes from CUT&Tag sequencing data (2 independent experiments). (J) Heatmap showing the genome-wide Spearman’s correlation between the H3Q5ser and H3cit modifications (2 independent experiments). (K and L) Heatmaps of H3cit (K) and H3Q5ser (L) peaks are shown on a genome-wide scale in HL-60 granulocytes (2 independent experiments). (M) CUT&Tag profiles of co-occupied NET-related genes including ITGB2, DNASE1, ITGAM, RIPK1, MPO, and AKT1 of H3cit and H3Q5ser modifications in HL-60 granulocytes (2 independent experiments).