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 language | English (US) |
|---|---|
| Pages (from-to) | 2550-2563 |
| Number of pages | 14 |
| Journal | Cancer Research |
| Volume | 80 |
| Issue number | 12 |
| DOIs | |
| State | Published - Jun 2020 |
Funding
This work was supported by the Northwestern University Zell scholar fund and grants from the NIH (R01CA154695). Support from National Nature Science Foundation of China (81130043) is acknowledged by Z. Liu. Support from NIH grants U54 HG008540 and P41 GM103712 is gratefully acknowledged by I. Bahar. We are grateful to Drs. Wade Harper and Jianping Jin for kindly providing the TAP purification vector. We appreciate the proteomic core at the University of Pittsburgh for mass spectrometry analyses. We thank all members of Wan, Liu, and Bahar laboratories for their helpful discussion.
ASJC Scopus subject areas
- Oncology
- Cancer Research
