EIF3H orchestrates hippo pathway-mediated oncogenesis via catalytic control of YAP stability

Zhuan Zhou, Honghong Zhou, Luca Ponzoni, Aiping Luo, Rui Zhu, Mingjing He, Yi Huang, Kun Liang Guan, Ivet Bahar, Zhihua Liu, Yong Wan*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2550-2563
Number of pages14
JournalCancer Research
Volume80
Issue number12
DOIs
StatePublished - Jun 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'EIF3H orchestrates hippo pathway-mediated oncogenesis via catalytic control of YAP stability'. Together they form a unique fingerprint.

Cite this