Serotonin sets up neutrophil extracellular traps to promote neuroendocrine prostate cancer metastasis in the liver
Dean G. Tang
Dean G. Tang
Published April 15, 2025
Citation Information: J Clin Invest. 2025;135(8):e191687. https://doi.org/10.1172/JCI191687.
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Commentary

Serotonin sets up neutrophil extracellular traps to promote neuroendocrine prostate cancer metastasis in the liver

Abstract

Castration-resistant prostate cancer frequently metastasizes to the liver, and prostate cancer liver metastases often present a neuroendocrine phenotype (i.e., neuroendocrine prostate cancer [NEPC]), but the underlying molecular underpinnings remain unclear. In this issue of the JCI, Liu et al. demonstrate that the neurotransmitter serotonin (also known as 5-hydroxytryptamine), produced by NEPC cells, gained access to and activated neutrophils by modifying histone 3 (H3) to form neutrophil extracellular traps, which in turn promoted NEPC macrometastases in the liver. The study suggests that blocking serotonin transport to neutrophils and inhibiting the enzymes that catalyze serotonin-mediated H3 modifications may represent alternative approaches to treating prostate cancer liver metastases.

Authors

Dean G. Tang

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Figure 1

Serotonin promotes NEPC metastasis in the liver via posttranslational modification of H3 in neutrophils and increases NET formation.

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Serotonin promotes NEPC metastasis in the liver via posttranslational mo...
(A) Primary PCa can metastasize to different parts of the body including bone, LNs, brain, lungs, and liver. The findings from Liu et al. (7) support a model in which AR– NEPC cells disseminate to the liver and secrete serotonin, which is taken up by neutrophils via SERT. Once in the neutrophils, serotonin mediates H3 serotonylation and citrullination, leading to neutrophil activation, NET formation, and subsequent NEPC macrometastasis in the liver. Notably, the antidepressant fluoxetine can inhibit SERT and may block liver metastasis. (B) The process of serotonylation is mediated by TGM2, while citrullination is mediated by PAD4. (C) Modification of core histones within the condensed nucleosome at H2A, H2B, H3, and H4 affects chromatin accessibility. Both posttranslational processes, serotonylation and citrullination, occur in the H3 N-terminal tail and act together to decondense and loosen chromatin. In particular, serotonylation modifies the fifth H3 residue Q5, and citrullination affects 3 arginine residues (i.e., R2, R8, and R17).