USP22 promotes melanoma and BRAF inhibitor resistance via YAP stabilization

Abstract

Yes-associated protein (YAP) is a conserved tran- scriptional coactivator that plays key roles in controlling organ size, tumorigenesis and drug resistance. Emerging evidence shows that YAP is overexpressed and associated with resis- tance to BRAF inhibitor treatment in melanoma. However, the mechanism accounting for YAP-overexpression in mela- noma is largely unknown. The present study characterized ubiquitin-specific peptidase 22 (USP22) as a deubiquitinase controlling YAP abundance and biological functions in melanoma. Using western blotting and immunohistochemical staining, it was found that the expression of USP22 and YAP was associated in melanoma cell lines and patient samples. Moreover, USP22 interacted with and deubiquitinated YAP to prevent YAP turnover. Depletion of USP22 decreased YAP expression, which in turn suppressed cell proliferation and tumorigenesis. Furthermore, overexpression of USP22 conferred vemurafenib resistance in a YAP-dependent manner. Overall, the present study revealed the important role of the USP22/YAP axis in melanoma and BRAF inhibitor resistance, and provides a rationale to target USP22/YAP for melanoma treatment.