RNF185 modulates JWA ubiquitination and promotes gastric cancer metastasis
RNF185 modulates JWA ubiquitination and promotes gastric cancer metastasis
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RNF185调节JWA泛素化并促进胃癌转移
DOI：
10.1016/j.bbadis.2018.02.013
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发表时间：
2018-05-01
影响因子：
6.2
通讯作者：
Zhou, Jianwei
中科院分区：
文献类型：
--
作者：
Qiu, Danping;Wang, Qiang;Zhou, Jianwei
胃癌（GC）是全世界最常见的恶性肿瘤之一。转移导致晚期胃癌患者预后不良。我们之前的研究表明，JWA 具有肿瘤抑制因子的功能，GC 组织中 JWA 的低表达与较短的总生存期 (OS) 以及患者的晚期临床病理特征显着相关。然而，JWA在癌症中失调的机制尚不清楚。在本研究中，我们发现E3泛素连接酶RNF185直接与JWA相互作用并促进其在K158位点泛素化，导致随后的降解。此外，GC患者肿瘤组织中RNF185的蛋白水平与JWA呈负相关。 RNF185 高表达与较短的 OS 显着相关。此外，RNF185表达增加可促进体外GC细胞迁移，并通过下调JWA表达促进体内GC转移。然而，这种影响被 JWA 的补充所逆转。总之，我们的研究结果强调了以下几点：(1) RNF185 通过泛素-蛋白酶体途径介导 JWA 降解，从而促进 GC 转移； (2) JWA的K158位点对其在GC细胞中泛素化至关重要。这些发现表明 RNF185 是一种新的候选预后标志物和 GC 的潜在治疗靶点。
Gastric cancer (GC) is one of the most common malignant cancers worldwide. Metastasis leads to poor prognoses in GC patients in advanced stages. Our previous studies have demonstrated that JWA functions as a tumour suppressor and that low expression of JWA in GC tissues is significantly correlated with shorter overall survival (OS) as well as with advanced clinicopathologic features in patients. However, the mechanism of dysregulation of JWA in cancers is not clear. In the present study, we found that an E3 ubiquitin ligase, RNF185, directly interacted with JWA and promoted its ubiquitination at the K158 site, resulting in subsequent degradation. Moreover, the protein level of RNF185 was negatively correlated with JWA in tumour tissues from GC patients. High RNF185 expression was significantly correlated with shorter OS. Additionally, increased RNF185 expression facilitated GC cell migration in vitro and promoted GC metastasis in vivo by downregulating JWA expression. However, this effect was reversed by replenishment of JWA. In conclusion, our findings highlight the following: (1) RNF185 promotes GC metastasis by mediating JWA degradation via a ubiquitin-proteasome pathway; (2) the K158 site of JWA is essential for its ubiquitination in GC cells. These findings suggest that RNF185 is a novel candidate prognostic marker and potential therapeutic target for GC.