Serotonin Modulates Lineage Plasticity in Neuroendocrine Prostate Cancer via Epigenetic Reprogramming
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.
Authors
- Ruitu Lyu (ORCID: https://orcid.org/0000-0003-4597-1604)
- Lisheng Zhang (ORCID: https://orcid.org/0000-0003-1872-9978)
- Jiahua Pan (ORCID: https://orcid.org/0000-0002-8559-7170)
- Han Li (ORCID: https://orcid.org/0000-0002-4350-6314)
- Yiyi Ji (ORCID: https://orcid.org/0000-0001-5598-0059)
- Zejun Yan (ORCID: https://orcid.org/0000-0002-8138-459X)
- Jiangbo Wei (ORCID: https://orcid.org/0000-0003-2691-6490)
- Hongyang Qian (ORCID: https://orcid.org/0000-0003-0560-1721)
- Cheng‐Wei Ju (ORCID: https://orcid.org/0000-0002-2250-8548)
- Yunzheng Liu (ORCID: https://orcid.org/0009-0003-0559-7440)
- Bo Liu (ORCID: https://orcid.org/0000-0002-2914-8530)
- Liang Dong (ORCID: https://orcid.org/0000-0001-7689-3237)
- Na Jing (ORCID: https://orcid.org/0009-0004-6029-2575)
- Shu‐Heng Jiang (ORCID: https://orcid.org/0000-0001-8516-6234)
- X F Liu (ORCID: https://orcid.org/0009-0007-0868-8312)
- Helen He Zhu (ORCID: https://orcid.org/0000-0003-0290-5527)
- Yizheng Xue (ORCID: https://orcid.org/0009-0000-3255-3150)
- Man Tsuey Tse (ORCID: https://orcid.org/0009-0002-3935-9638)
- Lei Chen (ORCID: https://orcid.org/0000-0002-7822-435X)
- Wei Xue (ORCID: https://orcid.org/0000-0003-0124-9433)
- Weiwei Zhang (ORCID: https://orcid.org/0000-0001-5525-2852)
- Liangliang Wang (ORCID: https://orcid.org/0000-0001-8340-5190)
- Qi Wang (ORCID: https://orcid.org/0000-0003-2044-9238)
- Yinjie Zhu
- Xinran Zhang (ORCID: https://orcid.org/0000-0001-6454-3467)
- Yi‐Qian Pan (ORCID: https://orcid.org/0009-0003-2516-2778)
- Peng Xia (ORCID: https://orcid.org/0000-0002-6046-3790)
- Kai Shen (ORCID: https://orcid.org/0000-0003-2491-5654)
- Ang Li (ORCID: https://orcid.org/0000-0001-7578-1911)
- Ruopeng Su (ORCID: https://orcid.org/0000-0002-8160-3959)
Institutions
- Ningbo University (CN)
- Chinese Academy of Social Sciences (CN)
- California Institute of Technology (US)
- Sun Yat-sen University (CN)
- National University of Singapore (SG)
- Duke University (US)
- Shanghai Jiao Tong University (CN)
- Hong Kong University of Science and Technology (HK)
- Renji Hospital (CN)
- Wuhan University (CN)
- University of Chicago (US)
- National University Cancer Institute, Singapore (SG)
- Shanghai Cancer Institute (CN)
- Zhongnan Hospital of Wuhan University (CN)
- Chinese Academy of Agricultural Engineering (CN)
- UPMC Hillman Cancer Center (US)
- Sun Yat-sen University Cancer Center (CN)
- Duke University Hospital (US)
- Ningbo University Affiliated Hospital (CN)
- Institute of Physics (CN)
- University of Chinese Academy of Sciences (CN)
- Ningbo First Hospital (CN)
- University of Pennsylvania (US)
- University of Hong Kong (HK)
- Philadelphia University (US)
Publication Details
- Journal
- Cancer Discovery
- Published
- 2025-12-19
- DOI
- https://doi.org/10.1158/2159-8290.cd-25-0974
- Citations
- 1
- Primary Topic
- Cancer, Stress, Anesthesia, and Immune Response
- Type
- article
- Field-Weighted Citation Impact
- 1.47