EIF3H Orchestrates Hippo Pathway–Mediated Oncogenesis via Catalytic Control of YAP Stability
| Autor: | Mingjing He, Zhihua Liu, Yong Wan, Rui Zhu, Kun-Liang Guan, Honghong Zhou, Ivet Bahar, Luca Ponzoni, Aiping Luo, Yi Huang, Zhuan Zhou |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research Carcinogenesis Eukaryotic Initiation Factor-3 Kaplan-Meier Estimate medicine.disease_cause Deubiquitinating enzyme Metastasis Mice 0302 clinical medicine Ubiquitin Breast Mastectomy Aged 80 and over YAP1 Deubiquitinating Enzymes biology medicine.diagnostic_test Protein Stability Chemistry Carcinoma Ductal Breast Middle Aged Prognosis Cell biology Molecular Docking Simulation Oncology 030220 oncology & carcinogenesis Female Signal Transduction Adult Proteolysis Breast Neoplasms Protein Serine-Threonine Kinases Disease-Free Survival Article Young Adult 03 medical and health sciences Cell Line Tumor medicine Animals Humans Hippo Signaling Pathway Neoplasm Invasiveness Adaptor Proteins Signal Transducing Aged Hippo signaling pathway Ubiquitination YAP-Signaling Proteins medicine.disease Disease Models Animal 030104 developmental biology Tumor progression Biocatalysis biology.protein Transcription Factors |
| Zdroj: | Cancer Res |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | EIF3H is presumed to be a critical translational initiation factor. Here, our unbiased screening for tumor invasion factors has identified an unexpected role for EIF3H as a deubiquitylating enzyme that dictates breast tumor invasion and metastasis by modulating the Hippo–YAP pathway. EIF3H catalyzed YAP for deubiquitylation, resulting in its stabilization. Structure-based molecular modeling and simulations coupled with biochemical characterization unveiled a unique catalytic mechanism for EIF3H in dissociating polyubiquitin chains from YAP through a catalytic triad consisting of Asp90, Asp91, and Gln121. Trp119 and Tyr 140 on EIF3H directly interacted with the N-terminal region of YAP1, facilitating complex formation of EIF3H and YAP1 for YAP1 deubiquitylation. Stabilization of YAP via elevated EIF3H promoted tumor invasion and metastasis. Interference of EIF3H-mediated YAP deubiquitylation blocked YAP-induced tumor progression and metastasis in breast cancer models. These findings point to a critical role for YAP regulation by EIF3H in tumor invasion and metastasis. Significance: This work demonstrates that EIF3H is a novel bona fide deubiquitinase that counteracts YAP ubiquitylation and proteolysis, and stabilization of YAP by EIF3H promotes tumor invasion and metastasis. |
| Databáze: | OpenAIRE |
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