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

17 Scopus citations


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
Issue number12
StatePublished - Jun 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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