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Blockade of deubiquitinase USP7 overcomes bortezomib resistance by suppressing NF‐κB signaling pathway in multiple myeloma
Author(s) -
Yao Yao,
Zhang Yan,
Shi Min,
Sun Yueyue,
Chen Chong,
Niu Mingshan,
Zhang Qi,
Zeng Lingyu,
Yao Ruosi,
Li Hujun,
Yang Jiajia,
Li Zhenyu,
Xu Kailin
Publication year - 2018
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1002/jlb.2a1017-420rr
Subject(s) - bortezomib , multiple myeloma , deubiquitinating enzyme , cancer research , pharmacology , downregulation and upregulation , blockade , biology , transfection , cell culture , receptor , immunology , biochemistry , gene , ubiquitin , genetics
The treatment of multiple myeloma (MM) with bortezomib (BTZ) is promising; however, the emergence of resistance is challenging in the clinical treatment. Thus, a novel targeted treatment or exploring the mechanism underlying BTZ resistance is an urgent requisite. The current data showed that high expression of USP7 in myeloma was a predictor of short overall survival and poor outcome. USP7 knockout significantly suppressed the colony formation, inhibited the proliferation of BTZ‐resistant MM cells even in the presence of growth factors, and overcame BTZ resistance. The knockout markedly inhibited the tumor growth and prolonged the survival of mice bearing BTZ‐resistant MM cells. Mechanistically, USP7 knockout remarkably increased the sensitivity to BTZ by stabilizing ΙκΒα and blocking the NF‐κB pathway. Not surprisingly, when IκBα was knocked down by siRNA transfection, the MM cells restored the BTZ resistance. Importantly, usage of USP7 inhibitors also suppressed the activation of NF‐κB and combination with BTZ triggered the synergistic antitumor activity in BTZ‐resistant MM cells. Taken together, this study provides the rationale for clinical protocols evaluating USP7 inhibition, alone and in combination with BTZ, to overcome BTZ resistance and improve the patient outcome in MM.