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The deubiquitinase USP10 regulates KLF4 stability and suppresses lung tumorigenesis.
Cell Death and Differentiation ( IF 12.4 ) Pub Date : 2019-11-20 , DOI: 10.1038/s41418-019-0458-7
Xingyun Wang 1, 2 , Shilin Xia 3 , Hongchang Li 4 , Xiang Wang 1 , Chaonan Li 4 , Yulin Chao 1 , Lingqiang Zhang 4 , Chuanchun Han 1
Affiliation  

Krüppel-like factor 4 (KLF4), a key transcription factor, acts as a multifunctional player involved in the progression of numerous aggressive cancers. The proteasome-dependent pathway is one of the main modalities in controlling KLF4 abundance at a posttranslational level. Although some of the ubiquitin ligases have been identified, the deubiquitinases of KLF4 and the regulatory function remain unexplored. Here, by screening ubiquitin-specific proteases that may interact with KLF4, we found ubiquitin-specific peptidase 10 (USP10) as a deubiquitinating enzyme for KLF4. Forced expression of USP10 remarkably increases KLF4 protein level by blocking the latter degradation, whereas the depletion of USP10 promotes KLF4 degradation and thus enhances tumorigenesis. Loss of USP10 in mice downregulates KLF4 expression and accelerates KrasG12D-driven lung adenocarcinoma initiation and progression. In addition, our data revealed that KLF4 can facilitate the transcription of tumor suppressor TIMP3 by directly binding to the TIMP3 promoter. Clinically, reduction of USP10 expression, concomitant with decreased KLF4 and TIMP3 abundance in carcinoma tissue, predicts poor prognosis of lung cancer patient. Taken together, our results demonstrate that USP10 is a critical regulator of KLF4, pinpointing USP10-KLF4-TIMP3 axis as a promising therapeutic target in lung cancer.

中文翻译:

去泛素酶 USP10 调节 KLF4 稳定性并抑制肺部肿瘤发生。

Krüppel 样因子 4 (KLF4) 是一种关键转录因子,作为多功能参与者参与多种侵袭性癌症的进展。蛋白酶体依赖性途径是在翻译后水平控制 KLF4 丰度的主要方式之一。尽管一些泛素连接酶已被鉴定,但 KLF4 的去泛素酶及其调节功能仍有待探索。在这里,通过筛选可能与 KLF4 相互作用的泛素特异性蛋白酶,我们发现泛素特异性肽酶 10 (USP10) 作为 KLF4 的去泛素化酶。USP10的强制表达通过阻止后者的降解而显着增加KLF4蛋白水平,而USP10的消耗则促进KLF4降解,从而增强肿瘤发生。小鼠中 USP10 的缺失会下调 KLF4 表达并加速 KrasG12D 驱动的肺腺癌的发生和进展。此外,我们的数据显示KLF4可以通过直接结合TIMP3启动子来促进肿瘤抑制因子TIMP3的转录。临床上,USP10表达的降低,伴随着癌组织中KLF4和TIMP3丰度的降低,预示着肺癌患者的不良预后。总而言之,我们的结果表明 USP10 是 KLF4 的关键调节因子,将 USP10-KLF4-TIMP3 轴确定为肺癌有希望的治疗靶点。
更新日期:2019-11-20
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