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

  • Nat Commun. 2024 Mar 21;15(1):2551. doi: 10.1038/s41467-024-46521-3.
Huilin Jin  #  1  2  3  4 ,  Xiaoling Huang  #  1  2  3 ,  Qihao Pan  #  2  3  5 ,  Ning Ma  1  2  3 ,  Xiaoshan Xie  1  2  3 ,  Yue Wei  1  2  3 ,  Fenghai Yu  1  2  3 ,  Weijie Wen  1  2  3 ,  Boyu Zhang  1  2  3 ,  Peng Zhang  1  2  3 ,  Xijie Chen  1  2  3  6 ,  Jie Wang  7 ,  Ran-Yi Liu  8 ,  Junzhong Lin  8 ,  Xiangqi Meng  9  10  11 ,  Mong-Hong Lee  12  13  14
Affiliations
  • 1. Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • 2. Guangdong Provincial Key laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • 3. Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • 4. Department of Hepatobiliary, Pancreatic and Splenic surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • 5. Department of Obstetrics and Gynecology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • 6. Department of Gastrointestinal Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
  • 7. Department of Radiation Oncology, Dalian Municipal Central Hospital, Dalian, China.
  • 8. State Key Laboratory of Oncology in South China & Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • 9. Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. [email protected].
  • 10. Guangdong Provincial Key laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. [email protected].
  • 11. Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. [email protected].
  • 12. Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. [email protected].
  • 13. Guangdong Provincial Key laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. [email protected].
  • 14. Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. [email protected].
  • # Contributed equally.
PMID: 38514606 DOI: 10.1038/s41467-024-46521-3
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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