USP35 activated by miR let-7a inhibits cell proliferation and NF-κB activation through stabilization of ABIN-2.
Ubiquitin specific protease 35 (USP35) is a member of deubiquitylases (DUBs). It remains largely unknown about the biological role and the regulation mechanism of USP35. Here, we first identified miR let-7a as a positive regulator of USP35 expression and showed that USP35 expression positively correlates with miR let-7a expression in different cancer cell lines and tissues. Then, we showed that USP35 expression was decreased dramatically in the tumor tissues compared with the adjacent non-cancerous tissues. USP35 overexpression inhibited cell proliferation in vitro and inhibited xenograft tumor growth in vivo. Furthermore, we revealed that USP35 acts as a functional DUB and stabilizes TNFAIP3 interacting protein 2 (ABIN-2) by promoting its deubiquitination. Functionally, both ABIN-2 and USP35 could inhibit TNFα-induced NF-κB activation and overexpression of ABIN-2 alleviated USP35-loss induced activation of NF-κB. Collectively, our data indicated that miR let-7a-regulated USP35 can inhibit NF-κB activation by deubiquitination and stabilization of ABIN-2 protein and eventually inhibit cell proliferation. Overall, our study provides a novel rationale of targeting miR let-7a-USP35-ABIN-2 pathway for the therapy of cancer patients.
Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan, Shandong, 250012, P.R. China.
Chunyan
C
Liu
Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan, Shandong, 250012, P.R. China.
Lina
L
Wang
Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan, Shandong, 250012, P.R. China.
Weiwen
W
Chen
Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan, Shandong, 250012, P.R. China.
Shihu
S
Zhao
Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan, Shandong, 250012, P.R. China.
Chunli
C
Yin
Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan, Shandong, 250012, P.R. China.
Yani
Y
Lin
Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan, Shandong, 250012, P.R. China.
Anli
A
Jiang
Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan, Shandong, 250012, P.R. China.
Pengju
P
Zhang
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D064593:Heterografts; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016133:Polymerase Chain Reaction; D014162:Transfection
D048868:Adaptor Proteins, Signal Transducing; D035683:MicroRNAs; D016328:NF-kappa B; C434062:TNIP2 protein, human; C487931:mirnlet7 microRNA, human; D010450:Endopeptidases; C000605806:USP35 protein, human
ABIN-2; NF-κB; USP35; deubiquitylase; miR let-7a