EIF3H Orchestrates Hippo Pathway-Mediated Oncogenesis via Catalytic Control of YAP Stability.
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.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Adult, Aged, Aged, 80 and over, Animals, Biocatalysis, Breast, Breast Neoplasms, Carcinogenesis, Carcinoma, Ductal, Breast, Cell Line, Tumor, Deubiquitinating Enzymes, Disease Models, Animal, Disease-Free Survival, Eukaryotic Initiation Factor-3, Female, Humans, Kaplan-Meier Estimate, Mastectomy, Mice, Middle Aged, Molecular Docking Simulation, Neoplasm Invasiveness, Prognosis, Protein Stability, Protein-Serine-Threonine Kinases, Signal Transduction, Transcription Factors, Ubiquitination, Young Adult
Adaptor Proteins, Signal Transducing, Adult, Aged, Aged, 80 and over, Animals, Biocatalysis, Breast, Breast Neoplasms, Carcinogenesis, Carcinoma, Ductal, Breast, Cell Line, Tumor, Deubiquitinating Enzymes, Disease Models, Animal, Disease-Free Survival, Eukaryotic Initiation Factor-3, Female, Humans, Kaplan-Meier Estimate, Mastectomy, Mice, Middle Aged, Molecular Docking Simulation, Neoplasm Invasiveness, Prognosis, Protein Stability, Protein-Serine-Threonine Kinases, Signal Transduction, Transcription Factors, Ubiquitination, Young Adult
Cancer Res
Date: Dec. 15, 2019
PubMed ID: 32269044
View in: Pubmed Google Scholar
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