MAPK/ERK通路
结直肠癌
癌症研究
癌症
信号转导
医学
生物
细胞生物学
内科学
作者
Huilin Jin,Xiaoling Huang,Qihao Pan,Ning Ma,Xiaoshan Xie,Wei Yue,Fenghai Yu,Weijie Wen,Boyu Zhang,Peng Zhang,Xijie Chen,Jie Wang,Ran‐yi Liu,Junzhong Lin,Xiangqi Meng,Mong Hong Lee
标识
DOI:10.1038/s41467-024-46521-3
摘要
Abstract Eukaryotic initiation translation factor 3 subunit h (EIF3H) plays critical roles in regulating translational initiation and predicts poor cancer prognosis, but the mechanism underlying EIF3H tumorigenesis remains to be further elucidated. Here, we report that EIF3H is overexpressed in colorectal cancer (CRC) and correlates with poor prognosis. Conditional Eif3h deletion suppresses colorectal tumorigenesis in AOM/DSS model. Mechanistically, EIF3H functions as a deubiquitinase for HAX1 and stabilizes HAX1 via antagonizing βTrCP-mediated ubiquitination, which enhances the interaction between RAF1, MEK1 and ERK1, thereby potentiating phosphorylation of ERK1/2. In addition, activation of Wnt/β-catenin signaling induces EIF3H expression. EIF3H/HAX1 axis promotes CRC tumorigenesis and metastasis in mouse orthotopic cancer model. Significantly, combined targeting Wnt and RAF1-ERK1/2 signaling synergistically inhibits tumor growth in EIF3H-high patient-derived xenografts. These results uncover the important roles of EIF3H in mediating CRC progression through regulating HAX1 and RAF1-ERK1/2 signaling. EIF3H represents a promising therapeutic target and prognostic marker in CRC.
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