Serotonin modulates lineage plasticity in neuroendocrine prostate cancer via epigenetic reprogramming

  • Cancer Discov. 2025 Dec 19. doi: 10.1158/2159-8290.CD-25-0974.
Yiyi Ji  1 ,  Cheng-Wei Ju  2 ,  Lei Chen  3 ,  Kai Shen  4 ,  Ruopeng Su  3 ,  Ang Li  3 ,  Xinyu Liu  3 ,  Bo Liu  3 ,  Xinran Zhang  5 ,  Ruitu Lyu  6 ,  Peng Xia  7 ,  Han Li  2 ,  Yiqian Pan  7 ,  Yunzheng Liu  8 ,  Man Hin Tse  9 ,  Yizheng Xue  10 ,  Hongyang Qian  11 ,  Na Jing  12 ,  Helen He Zhu  3 ,  Liangliang Wang  13 ,  Li-Sheng Zhang  2 ,  Shu-Heng Jiang  14 ,  Weiwei Zhang  15 ,  Liang Dong  3 ,  Zejun Yan  16 ,  Jiahua Pan  12 ,  Yinjie Zhu  17 ,  Jiangbo Wei  2 ,  Qi Wang  3 ,  Wei Xue  15
Affiliations
  • 1. University of Chicago Chicago United States.
  • 2. University of Chicago Chicago, IL Singapore.
  • 3. Shanghai Jiao Tong University Shanghai China.
  • 4. Department of Urology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200120, China. China.
  • 5. National University of Singapore Chicago, IL Singapore.
  • 6. Department of Chemistry, The University of Chicago, Chicago, IL 60637, USA Chicago United States.
  • 7. University of Chicago United States.
  • 8. California Institute of Technology United States.
  • 9. Hong Kong University of Science and Technology Hong Kong Hong Kong.
  • 10. University of Pennsylvania Philadelphia, PA United States.
  • 11. Department of Urology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200120, China. 6. Department of Pathology, Duke University, Durham 26605, NC, USA. United States.
  • 12. Shanghai Jiao Tong University China.
  • 13. Chinese Academy of Sciences Beijing China.
  • 14. Shanghai Cancer Institute Shanghai China.
  • 15. Shanghai Jiao Tong University Shanghai, Shanghai China.
  • 16. Ningbo University Ningbo China.
  • 17. Renji Hospital China.
PMID: 41416996 DOI: 10.1158/2159-8290.CD-25-0974
Abstract

Neuroendocrine prostate Cancer (NEPC) is an aggressive, therapy-resistant subtype of prostate Cancer characterized by lineage plasticity. While metabolic and signaling molecules are increasingly recognized as modulators of tumor progression, their role in cell fate transition remains unclear. NE tumors produce and accumulate serotonin, a neurotransmitter that regulates diverse physiological processes. Here, we identify a tumor-intrinsic serotonin axis as key driver of NEPC lineage commitment and progression. NEPC endogenously synthesize serotonin via aromatic L-amino acid decarboxylase (DDC) and reuptake through the transporter SLC6A4. Mechanistically, high level of intracellular serotonin promotes histone serotonylation at H3K4me3Q5, reconfiguring the H3K4me3 chromatin landscape and downstream gene expression, which drives induced NE differentiation and is associated with suppressed Androgen Receptor signaling. Pharmacological inhibition of 5-HT synthesis using the FDA-approved DDC inhibitor carbidopa significantly impairs tumor growth and prolongs survival in both genetically engineered and patient-derived xenograft models, highlighting histone serotonylation as a druggable vulnerability in NEPC.

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