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

Author

Listed:
  • Huilin Jin

    (Sun Yat-sen University
    Sun Yat-sen University
    Sun Yat-sen University
    Sun Yat-sen University)

  • Xiaoling Huang

    (Sun Yat-sen University
    Sun Yat-sen University
    Sun Yat-sen University)

  • Qihao Pan

    (Sun Yat-sen University
    Sun Yat-sen University
    Sun Yat-sen University)

  • Ning Ma

    (Sun Yat-sen University
    Sun Yat-sen University
    Sun Yat-sen University)

  • Xiaoshan Xie

    (Sun Yat-sen University
    Sun Yat-sen University
    Sun Yat-sen University)

  • Yue Wei

    (Sun Yat-sen University
    Sun Yat-sen University
    Sun Yat-sen University)

  • Fenghai Yu

    (Sun Yat-sen University
    Sun Yat-sen University
    Sun Yat-sen University)

  • Weijie Wen

    (Sun Yat-sen University
    Sun Yat-sen University
    Sun Yat-sen University)

  • Boyu Zhang

    (Sun Yat-sen University
    Sun Yat-sen University
    Sun Yat-sen University)

  • Peng Zhang

    (Sun Yat-sen University
    Sun Yat-sen University
    Sun Yat-sen University)

  • Xijie Chen

    (Sun Yat-sen University
    Sun Yat-sen University
    Sun Yat-sen University
    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
    Sun Yat-sen University
    Sun Yat-sen University)

  • Mong-Hong Lee

    (Sun Yat-sen University
    Sun Yat-sen University
    Sun Yat-sen University)

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.

Suggested Citation

  • 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 & Mong, 2024. "The EIF3H-HAX1 axis increases RAF-MEK-ERK signaling activity to promote colorectal cancer progression," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46521-3
    DOI: 10.1038/s41467-024-46521-3
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