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. Epub 2024 Aug 2.

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.

MeSH terms

  • Animals
  • Cancer-Associated Fibroblasts* / metabolism
  • Cancer-Associated Fibroblasts* / pathology
  • Cell Line, Tumor
  • Cell Proliferation*
  • Colorectal Neoplasms* / genetics
  • Colorectal Neoplasms* / metabolism
  • Colorectal Neoplasms* / pathology
  • Histones / metabolism
  • Humans
  • Male
  • Mice
  • Receptors, Serotonin / genetics
  • Receptors, Serotonin / metabolism
  • Serotonin* / metabolism
  • Tryptophan Hydroxylase* / genetics
  • Tryptophan Hydroxylase* / metabolism

Substances

  • Serotonin
  • Tryptophan Hydroxylase
  • Histones
  • TPH1 protein, human
  • Receptors, Serotonin