累积的研究强调了 5-羟色胺 (5-HT) 或血清素在癌症生物学，特别是结直肠癌 (CRC) 中的多种作用。虽然 5-HT 主要通过与各种 5-HT 受体结合发挥作用，但受体独立机制（例如血清素化）仍不清楚。这项研究表明，通过 Tph1 基因沉默或使用选择性 TPH1 抑制剂来消耗 5-HT，可以有效减少 CRC 肿瘤的生长。有趣的是，尽管结直肠癌中存在内在的 5-HT 合成，但介导 5-HT 促癌功能的是循环 5-HT。阻断 5-HT 受体的功能表明 5-HT 在 CRC 中的致癌作用通过与其受体分开的机制发挥作用。相反，在 CRC 细胞和癌症相关成纤维细胞 (CAF) 中发现了组蛋白 H3Q5 (H3Q5ser) 的血清酰化。 H3Q5ser 触发 CAF 表型转变为炎症样 CAF (iCAF) 亚型，进一步增强 CRC 细胞增殖、侵袭特征和巨噬细胞极化。敲除 5-HT 转运蛋白 SLC22A3 或抑制 TGM2 可降低 CRC 中 H3Q5ser 水平并逆转 CAF 的促肿瘤表型。总的来说，这项研究揭示了 5-HT 在 CRC 进展中的血清素化依赖性机制，为针对 CRC 治疗的血清素途径的潜在治疗策略提供了见解。版权所有 © 2024 Elsevier B.V. 保留所有权利。

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.Copyright © 2024 Elsevier B.V. All rights reserved.