Serotonin receptor HTR2B facilitates colorectal cancer metastasis via CREB1-ZEB1 axis mediated epithelial-mesenchymal transition.

Abstract

A number of neurotransmitters have been detected in tumor microenvironment and proved to modulate cancer oncogenesis and progression. We previously found that biosynthesis and secretion of neurotransmitter 5-hydroxytryptamine (5-HT) was elevated in colorectal cancer (CRC) cells. In this study, we discovered that the HTR2B receptor of 5-HT was highly expressed in CRC tumor tissues, which was further identified as a strong risk factor for CRC prognostic outcomes. Both pharmacological blocking and genetic knocking down HTR2B impaired migration of CRC cell, as well as the epithelial-mesenchymal transition (EMT) process. Mechanistically, HTR2B signaling induced ribosomal protein S6 kinase B1 (S6K1) activation via Akt/mTOR pathway, which triggered cAMP responsive element binding protein 1 (CREB1) phosphorylation (Ser 133) and translocation into the nucleus, then the phosphorylated CREB1 acts as an activator for ZEB1 transcription after binding to CREB1 half-site (GTCA) at ZEB1 promoter. As a key regulator of EMT, ZEB1 therefore enhances migration and EMT process in CRC cells. We also found that HTR2B specific antagonist (RS127445) treatment significantly ameliorated metastasis and reversed EMT process in both HCT116 cell tail-vein-injected pulmonary metastasis and CT26 cell intrasplenic-injected hepatic metastasis mouse models. Implications: These findings uncover a novel regulatory role of HTR2B signaling on CRC metastasis, which provide experimental evidences for potential HTR2B-targeted anti-CRC metastasis therapy.