Journal article
EIF3H Orchestrates Hippo Pathway-Mediated Oncogenesis via Catalytic Control of YAP Stability
Cancer research (Chicago, Ill.), Vol.80(12), pp.2550-2563
06/15/2020
DOI: 10.1158/0008-5472.CAN-19-3718
PMCID: PMC7316131
PMID: 32269044
Abstract
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.
Details
- Title: Subtitle
- EIF3H Orchestrates Hippo Pathway-Mediated Oncogenesis via Catalytic Control of YAP Stability
- Creators
- Zhuan Zhou - Northwestern UniversityHonghong Zhou - Peking Union Medical College HospitalLuca Ponzoni - University of PittsburghAiping Luo - Chinese Academy of Medical Sciences & Peking Union Medical CollegeRui Zhu - Peking Union Medical College HospitalMingjing He - University of PittsburghYi Huang - University of PittsburghKun-Liang Guan - University of California, San DiegoIvet Bahar - University of PittsburghZhihua Liu - Peking Union Medical College HospitalYong Wan - Northwestern University
- Resource Type
- Journal article
- Publication Details
- Cancer research (Chicago, Ill.), Vol.80(12), pp.2550-2563
- Publisher
- Amer Assoc Cancer Research
- DOI
- 10.1158/0008-5472.CAN-19-3718
- PMID
- 32269044
- PMCID
- PMC7316131
- ISSN
- 0008-5472
- eISSN
- 1538-7445
- Number of pages
- 14
- Grant note
- R01CA154695; U54 HG008540; P41 GM103712 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA 81130043 / National Nature Science Foundation of China; National Natural Science Foundation of China (NSFC) Northwestern University Zell scholar fund
- Language
- English
- Date published
- 06/15/2020
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984383900102771
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