The EIF3H-HAX1 axis increases RAF-MEK-ERK signaling activity to promote colorectal cancer progression

Huilin Jin, Xiaoling Huang, Qihao Pan, Ning Ma, Xiaoshan Xie, Yue Wei, Fenghai Yu, Weijie Wen, Boyu Zhang, Peng Zhang, Xijie Chen, Jie Wang, Ran-yi Liu, Junzhong Lin, Xiangqi Meng () and Mong-Hong Lee ()
Additional contact information
Huilin Jin: Sun Yat-sen University
Xiaoling Huang: Sun Yat-sen University
Qihao Pan: Sun Yat-sen University
Ning Ma: Sun Yat-sen University
Xiaoshan Xie: Sun Yat-sen University
Yue Wei: Sun Yat-sen University
Fenghai Yu: Sun Yat-sen University
Weijie Wen: Sun Yat-sen University
Boyu Zhang: Sun Yat-sen University
Peng Zhang: Sun Yat-sen University
Xijie Chen: Sun Yat-sen University
Jie Wang: Dalian Municipal Central Hospital
Ran-yi Liu: Sun Yat-sen University Cancer Center
Junzhong Lin: Sun Yat-sen University Cancer Center
Xiangqi Meng: Sun Yat-sen University
Mong-Hong Lee: Sun Yat-sen University

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-46521-3

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