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 8

The SERT inhibitor Fluox represses NET formation and liver metastasis in NE cancers.

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The SERT inhibitor Fluox represses NET formation and liver metastasis in...
(A–C) The SERT inhibitor Fluox suppressed liver metastasis (A) in mice i.v. inoculated with Rb1Δ/Δ Trp53Δ/Δ, as exemplified by decreased liver weights (B) and number of metastasis foci (C) compared with vehicle-treated mice (n = 5 mice per group). (D and E) IF staining images (D) and quantification results (E) showing decreased histone serotonylation (H3Q5ser+) in hepatic neutrophils (MPO+) in Rb1Δ/Δ Trp53Δ/Δ–inoculated mice upon treatment with Fluox as compared with vehicle treatment (n = 5 mice per group). Scale bars: 1.5 mm. (F and G) IF images (F) and quantification results (G) of neutrophil-derived (MPO+-derived) NETs (H3Cit) in Rb1Δ/Δ Trp53Δ/Δ–inoculated mice in response to vehicle or Fluox treatment (n = 5 mice per group). Scale bars: 50 μm. (H–J) H&E-stained images (H) and quantification results showing decreased metastasis foci numbers (I) in i.v. TT cell–inoculated mice following treatment with Fluox compared with their vehicle-treated counterparts (n = 8 mice per group). Scale bars: 1 mm. (K and L) IF staining images (K) and quantification results (L) showing decreased H3Q5ser levels in MPO+ neutrophils in the liver sections of TT cell-inoculated mice upon treatment with Fluox versus treatment with vehicle (n = 8 mice per group). Scale bars: 50 μm. (M and N) IF images (M) and quantification (N) of NETs in TT-inoculated mice in response to vehicle or Fluox treatment (n = 8 mice per group). Scale bars: 50 μm. *P < 0.05, **P < 0.01, and ***P < 0.001, by 2-tailed Student’s t test (B, C, E, J, L, and N) and Mann-Whitney U test (G and I). Data are presented as the mean ± SEM.