Ubiquitin-specific protease 4 controls metastatic potential through β-catenin stabilization in brain metastatic lung adenocarcinoma.
Ubiquitin-specific protease 4 controls metastatic potential through β-catenin stabilization in brain metastatic lung adenocarcinoma.
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DOI：
10.1038/srep21596
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发表时间：
2016-02-17
影响因子：
4.6
通讯作者：
Kim HH
中科院分区：
文献类型：
--
作者：
Hwang SJ;Lee HW;Kim HR;Lee H;Shin CH;Yun SI;Lee DH;Kim DH;Kim KK;Joo KM;Kim HH
脑转移是最常见的颅内癌类型，也是癌症相关死亡的主要原因。脑转移主要起源于肺癌。使用先前建立的体外脑转移模型，我们发现脑转移PC14PE6/LvBr4细胞比亲本PC14PE6细胞表现出更高的β-连环蛋白表达和更高的迁移活性。 β-连环蛋白的敲低显着抑制了 PC14PE6/LvBr4 细胞的运动性和侵袭性，表明 β-连环蛋白参与控制转移潜能。由于 β-连环蛋白蛋白增加而其 mRNA 水平没有显着变化，因此研究了 β-连环蛋白稳定性增加的机制。我们发现泛素特异性蛋白酶 4 (USP4) 最近被鉴定为 β-连环蛋白特异性去泛素化酶，在 PC14PE6/LvBr4 细胞中高表达，并参与 β-连环蛋白稳定性的增加。与 β-连环蛋白敲低类似，USP4 沉默的 PC14PE6/LvBr4 细胞显示出迁移和侵袭能力下降。此外，敲除USP4和β-连环蛋白可抑制PC14PE6/LvBr4细胞中的集落形成并通过下调ZEB1诱导间质-上皮转化。使用生物发光成像，我们发现 USP4 的敲低可抑制体内脑转移，并显着提高总体生存率和无脑转移生存率。综上所述，我们的结果表明 USP4 是肺腺癌患者脑转移的一个有前途的治疗靶点。
Brain metastasis is the most common type of intracranial cancer and is the main cause of cancer-associated mortality. Brain metastasis mainly originates from lung cancer. Using a previously established in vitro brain metastatic model, we found that brain metastatic PC14PE6/LvBr4 cells exhibited higher expression of β-catenin and increased migratory activity than parental PC14PE6 cells. Knockdown of β-catenin dramatically suppressed the motility and invasiveness of PC14PE6/LvBr4 cells, indicating β-catenin is involved in controlling metastatic potential. Since β-catenin protein was increased without a significant change in its mRNA levels, the mechanism underlying increased β-catenin stability was investigated. We found that ubiquitin-specific protease 4 (USP4), recently identified as a β-catenin-specific deubiquitinylating enzyme, was highly expressed in PC14PE6/LvBr4 cells and involved in the increased stability of β-catenin protein. Similar to β-catenin knockdown, USP4-silenced PC14PE6/LvBr4 cells showed decreased migratory and invasive abilities. Moreover, knockdown of both USP4 and β-catenin inhibited clonogenicity and induced mesenchymal-epithelial transition by downregulating ZEB1 in PC14PE6/LvBr4 cells. Using bioluminescence imaging, we found that knockdown of USP4 suppressed brain metastasis in vivo and significantly increased overall survival and brain metastasis-free survival. Taken together, our results indicate that USP4 is a promising therapeutic target for brain metastasis in patients with lung adenocarcinoma.