ECD promotes gastric cancer metastasis by blocking E3 ligase ZFP91-mediated hnRNP F ubiquitination and degradation.
ECD promotes gastric cancer metastasis by blocking E3 ligase ZFP91-mediated hnRNP F ubiquitination and degradation.
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ECD通过阻断E3连接酶ZFP91介导的hnRNP F泛素化和降解来促进胃癌转移。
DOI：
10.1038/s41419-018-0525-x
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发表时间：
2018-05-01
影响因子：
9
通讯作者：
Yan GR
中科院分区：
文献类型：
--
作者：
Xu SH;Zhu S;Wang Y;Huang JZ;Chen M;Wu QX;He YT;Chen D;Yan GR
果蝇无蜕皮基因（ECD）的人类同源性是胚胎发育和细胞周期进展所必需的；然而，它在癌症进展和转移中的作用尚不清楚。本研究中，我们发现ECD在胃癌（GC）中经常过表达，尤其是在转移性胃癌中，并且与胃癌患者临床预后差相关。沉默ECD抑制GC在体外的迁移和侵袭以及体内的转移，而过表达ECD则促进GC的迁移和侵袭。ECD通过保护hnRNP F免于泛素化和降解而促进GC的侵袭和转移。我们确定ZFP91是E3泛素连接酶，它负责hnRNP F在Lys 185处的泛素化和蛋白酶体降解。ECD通过n端STG1结构域（13-383aa）与hnRNP F竞争性结合，阻止hnRNP F与ZFP91相互作用，从而阻止ZFP91介导的hnRNP F泛素化和蛋白酶体降解。总之，我们的研究结果表明，ECD通过阻止E3连接酶zfp91介导的hnRNP F泛素化和降解来促进癌症的侵袭和转移，这表明ECD可能是胃癌患者预后不良的标志和潜在的治疗靶点。
The human ortholog of the Drosophila ecdysoneless gene (ECD) is required for embryonic development and cell-cycle progression; however, its role in cancer progression and metastasis remains unclear. Here, we found that ECD is frequently overexpressed in gastric cancer (GC), especially in metastatic GC, and is correlated with poor clinical outcomes in GC patients. Silencing ECD inhibited GC migration and invasion in vitro and metastasis in vivo, while ECD overexpression promoted GC migration and invasion. ECD promoted GC invasion and metastasis by protecting hnRNP F from ubiquitination and degradation. We identified ZFP91 as the E3 ubiquitin ligase that is responsible for hnRNP F ubiquitination at Lys 185 and proteasomal degradation. ECD competitively bound to hnRNP F via the N-terminal STG1 domain (13-383aa), preventing hnRNP F from interacting with ZFP91, thus preventing ZFP91-mediated hnRNP F ubiquitination and proteasomal degradation. Collectively, our findings indicate that ECD promotes cancer invasion and metastasis by preventing E3 ligase ZFP91-mediated hnRNP F ubiquitination and degradation, suggesting that ECD may be a marker for poor prognosis and a potential therapeutic target for GC patients.
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影响因子：
24.5
作者：
Deng N;Goh LK;Wang H;Das K;Tao J;Tan IB;Zhang S;Lee M;Wu J;Lim KH;Lei Z;Goh G;Lim QY;Tan AL;Sin Poh DY;Riahi S;Bell S;Shi MM;Linnartz R;Zhu F;Yeoh KG;Toh HC;Yong WP;Cheong HC;Rha SY;Boussioutas A;Grabsch H;Rozen S;Tan P
通讯作者：
Tan P
影响因子：
4.8
作者：
Garneau, D;Revil, T;Chabot, B
通讯作者：
Chabot, B
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8.8
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Tamayo JV;Teramoto T;Chatterjee S;Hall TMT;Gavis ER
通讯作者：
Gavis ER
影响因子：
3.7
作者：
Kim JH;Gurumurthy CB;Band H;Band V
通讯作者：
Band V
影响因子：
24.5
作者：
Hong, Xuehui;Song, Ruipeng;Zhang, Zhiyong
通讯作者：
Zhang, Zhiyong