The deubiquitylase USP2 maintains ErbB2 abundance via counteracting endocytic degradation and represents a therapeutic target in ErbB2-positive breast cancer
Open Access
- 23 April 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cell Death & Differentiation
- Vol. 27 (9), 2710-2725
- https://doi.org/10.1038/s41418-020-0538-8
Abstract
ErbB2 overexpression identifies a subclass of breast cancer as ErbB2-positive that is frequently associated with poor prognosis. Current ErbB2-targeted therapies have profoundly improved patient outcomes, but mutations occurring in ErbB2 have been shown to confer drug resistance. Induction of ErbB2 degradation was proposed as an intriguing strategy to battle with ErbB2-positive breast cancer and reduced mutation-incurred drug resistance. Although multiple HSP90 inhibitors have been demonstrated to effectively trigger ErbB2 degradation, none succeeded in the clinical evaluations. To develop novel ErbB2-targeting strategies, we investigated the endocytic degradation and reversible ubiquitylation of ErbB2 in breast cancer. In this study, we reveal that HSP90 inhibition leads to efficient ubiquitylation and endocytic degradation of ErbB2 through the canonical endo-lysosomal route. USP2 associates with internalized ErbB2 and prevents its lysosomal sorting and degradation via exerting deubiquitylase activity. Accordingly, the USP2 inhibitor ML364 is capable of inducing ErbB2 ubiquitylation and accelerating its turnover. ML364 potentiates the pro-degradation effects of HSP90 inhibitors on ErbB2 and hence sensitizes ErbB2-positive breast cancer cells to HSP90 inhibition. The combination of USP2 and HSP90 inhibitors effectively restrains ErbB2-positive breast cancer xenograft growth in vivo. Based on these observations, we conclude that USP2 safeguards ErbB2 surface levels by antagonizing its ubiquitylation-mediated endocytic degradation, which can be exploited to design novel therapeutic strategies against ErbB2-driven malignancies as combinatorial treatment with HSP90 inhibitors.Funding Information
- National Natural Science Foundation of China (81301901)
This publication has 53 references indexed in Scilit:
- The HSP90 inhibitor geldanamycin perturbs endosomal structure and drives recycling ErbB2 and transferrin to modified MVBs/lysosomal compartmentsMolecular Biology of the Cell, 2013
- Endocytosis and Signaling: Cell Logistics Shape the Eukaryotic Cell PlanPhysiological Reviews, 2012
- Ubiquitination-deubiquitination balance dictates ligand-stimulated PTHR sortingJournal of Bone and Mineral Research, 2011
- Feedback regulation of EGFR signalling: decision making by early and delayed loopsNature Reviews Molecular Cell Biology, 2011
- Suppression of Cancer Cell Growth by Promoting Cyclin D1 DegradationMolecular Cell, 2009
- Inhibitors of HSP90 block p95-HER2 signaling in Trastuzumab-resistant tumors and suppress their growthOncogene, 2009
- Endocytic Down-Regulation of ErbB2 Is Stimulated by Cleavage of Its C-TerminusMolecular Biology of the Cell, 2007
- Epidermal growth factor receptor mutations in lung cancerNature Reviews Cancer, 2007
- EGF–ERBB signalling: towards the systems levelNature Reviews Molecular Cell Biology, 2006
- Drug-induced ubiquitylation and degradation of ErbB receptor tyrosine kinases: implications for cancer therapyThe EMBO Journal, 2002