2. Academic Validation
  3. Serotonylation in tumor-associated fibroblasts contributes to the tumor-promoting roles of serotonin in colorectal cancer

Serotonylation in tumor-associated fibroblasts contributes to the tumor-promoting roles of serotonin in colorectal cancer

  • Cancer Lett. 2024 Sep 28:600:217150. doi: 10.1016/j.canlet.2024.217150.
Tianlong Ling 1,  Zhanghan Dai 2,  Houming Wang 3,  Tran Trung Kien 4,  Rong Cui 5,  Tachung Yu 6,  Jianjun Chen 7
Affiliations

Affiliations

  • 1 Department of Gastrointestinal Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
  • 2 Department of Gastroenterology and Hepatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
  • 3 Department of General Surgery, Jiading Hospital of Traditional Chinese Medicine, Jiading District, Shanghai, China.
  • 4 Oncology Department, University Medical Shing Mark Hospital, 1054 Highway 51, Long Binh Tan Ward, Bien Hoa City, Dong Nai, Viet Nam.
  • 5 Department of Gastrointestinal Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China. Electronic address: drcuirong@163.com.
  • 6 Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China. Electronic address: yutachung@163.com.
  • 7 Department of Gastrointestinal Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China. Electronic address: skyjjchen@sohu.com.
PMID: 39097134 DOI: 10.1016/j.canlet.2024.217150
Abstract

Accumulated studies have highlighted the diverse roles of 5-hydroxytryptamine (5-HT), or serotonin, in Cancer biology, particularly in colorectal Cancer (CRC). While 5-HT primarily exerts its effects through binding to various 5-HT receptors, receptor-independent mechanisms such as serotonylation remain unclear. This study revealed that depleting 5-HT, either through genetic silencing of Tph1 or using a selective TPH1 inhibitor, effectively reduced the growth of CRC tumors. Interestingly, although intrinsic 5-HT synthesis exists in CRC, it is circulating 5-HT that mediates the cancer-promoting function of 5-HT. Blocking the function of 5-HT receptors showed that the oncogenic roles of 5-HT in CRC operate through a mechanism that is separate from its receptor. Instead, serotonylation of histone H3Q5 (H3Q5ser) was found in CRC cells and cancer-associated fibroblasts (CAFs). H3Q5ser triggers a phenotypic switch of CAFs towards an inflammatory-like CAF (iCAF) subtype, which further enhances CRC cell proliferation, invasive characteristics, and macrophage polarization. Knockdown of the 5-HT transporter SLC22A3 or inhibition of TGM2 reduces H3Q5ser levels and reverses the tumor-promoting phenotypes of CAFs in CRC. Collectively, this study sheds light on the serotonylation-dependent mechanisms of 5-HT in CRC progression, offering insights into potential therapeutic strategies targeting the serotonin pathway for CRC treatment.

Keywords

Serotonin transporter; Serotonylation; Transglutaminases; Tumor-associated macrophages.

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