The molecular mechanism of liquidambaric acid inhibiting colorectal cancer by targeting TRAF6 to regulate Hippo/YAP signaling pathway
- VernacularTitle:路路通酸靶向TRAF6调控Hippo/YAP信号通路抗结直肠癌的分子机制
- Author:
Wei-wei ZHAO
1
;
Shi-cheng ZHENG
1
;
Tian-yi ZHANG
1
;
Jia-yu XIONG
1
;
Yi QU
1
;
Xi-song KE
1
;
Rong YAN
1
Author Information
- Publication Type:Journal Article
- Keywords: colorectal cancer; liquidambaric acid; TRAF6; Hippo/YAP signaling pathway; Wnt/β-cate-nin signaling pathway; TRAF2
- From: Chinese Pharmacological Bulletin 2025;41(8):1463-1469
- CountryChina
- Language:Chinese
- Abstract: Aim To elucidate the molecular mecha-nism underlying the inhibitory effect of liquidambaric acid(LDA)targeting TNF receptor associated factor 6(TRAF6)in colorectal cancer.Methods This study employed microscale thermophoresis(MST),drug af-finity responsive target stability assay(DARTS)and cellular thermal shift assay(CETSA)to confirm the direct binding of LDA to TRAF6.Additionally,we generated TRAF6 knockout colorectal cancer HCT116 cells using CRISPR/Cas9 technology,and assessed the impact of LDA on TRAF6-regulated Hippo/YAP and Wnt signaling pathways through immunofluorescence a-nalysis and TOPFlash/Renilla luciferase reporter sys-tem.Co-IP and proximity ligation assays(PLA)were conducted to investigate LDA-regulated TRAF6 pro-tein-protein interactions and elucidate molecular mech-anisms.Results The direct binding of LDA to TRAF6 was confirmed in cell lysates and living cells.LDA promoted TRAF6-dependent nuclear translocation of YAP in colorectal cancer cells,and inhibited Wnt signaling by overexpressing TRAF6.Co-IP and PLA revealed that TRAF6 formed a tripartite complex with YAP and β-catenin in colon cancer cells,where TRAF6 was a key scaffolding protein of the tripartite complex.LDA disrupted the interactions between the TRAF domain of TRAF6 and YAP,as well as YAP and β-catenin.Conclusion LDA regulates Hippo/YAP signaling pathway by targeting TRAF6 and inhib-its colorectal cancer.
