USP35 activated by miR let-7a inhibits cell proliferation and NF-κB activation through stabilization of ABIN-2.
USP35 activated by miR let-7a inhibits cell proliferation and NF-κB activation through stabilization of ABIN-2.
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miR let-7a 激活的 USP35 通过稳定 ABIN-2 抑制细胞增殖和 NF-κB 激活
DOI：
10.18632/oncotarget.4451
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发表时间：
2015-09-29
期刊：
影响因子：
--
通讯作者：
Zhang P
中科院分区：
文献类型：
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作者：
Liu C;Wang L;Chen W;Zhao S;Yin C;Lin Y;Jiang A;Zhang P
泛素特异性蛋白酶35（USP 35）是去泛素化酶（DUBs）的成员。关于USP 35的生物学作用和调节机制，在很大程度上仍然未知。在这里，我们首先确定了miR let-7a作为USP 35表达的正调节因子，并表明在不同的癌细胞系和组织中USP 35表达与miR let-7a表达正相关。然后，我们发现USP 35的表达显着降低，在肿瘤组织与相邻的非癌组织相比。USP 35过表达在体外抑制细胞增殖并在体内抑制异种移植肿瘤生长。此外，我们发现USP 35作为功能性DUB并通过促进其去泛素化来稳定TNFAIP 3相互作用蛋白2（ABIN-2）。在功能上，ABIN-2和USP 35均能抑制TNFα诱导的NF-κB活化，ABIN-2过表达可减轻USP 35缺失诱导的NF-κB活化。总之，我们的数据表明，miR let-7a调节的USP 35可以通过去泛素化和ABIN-2蛋白的稳定来抑制NF-κB活化，并最终抑制细胞增殖。总体而言，我们的研究为靶向miR let-7a-USP 35-ABIN-2途径治疗癌症患者提供了新的理论基础。
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.