CDK5/FBW7-dependent ubiquitination and degradation of EZH2 inhibits pancreatic cancer cell migration and invasion
CDK5/FBW7-dependent ubiquitination and degradation of EZH2 inhibits pancreatic cancer cell migration and invasion
复制标题
CDK5/FBW7依赖性EZH2泛素化和降解抑制胰腺癌细胞迁移和侵袭
DOI：
10.1074/jbc.m116.764407
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发表时间：
2017-04-14
影响因子：
4.8
通讯作者：
Wu, Heshui
中科院分区：
文献类型：
--
作者：
Jin, Xin;Yang, Chong;Wu, Heshui
胰腺癌是最致命的癌症类型之一。zeste同源物2的增强子（Enhancer of zeste homolog 2, EZH2）是一种在胰腺癌中过表达的致癌蛋白，EZH2可能是治疗胰腺癌的潜在靶点。尽管在了解EZH2在癌细胞中的功能和调控方面已经取得了重大进展，但EZH2在癌细胞中的翻译后调控尚不清楚。F-box和WD重复结构域7 （FBW7）通过靶向多种癌蛋白底物进行泛素化和降解，作为肿瘤抑制因子。本研究证明EZH2是胰腺癌细胞中FBW7的真正底物。我们提供的证据表明，活化的CDK5激酶参与了fbw7介导的降解所需的EZH2磷酸化。我们进一步发现FBW7通过降解胰腺癌细胞中的EZH2抑制肿瘤的迁移和侵袭，从而抑制EZH2活性。此外，免疫组织化学分析显示，在一组人胰腺癌标本中，EZH2蛋白的表达与FBW7蛋白水平呈负相关。总之，我们的研究结果表明，FBW7是一种新的EZH2 E3连接酶，可以调节胰腺癌中EZH2蛋白的水平，代表了有效治疗胰腺癌的可行策略。
Pancreatic cancer is one of the most lethal cancer types. Enhancer of zeste homolog 2 (EZH2) is an oncogenic protein overexpressed in pancreatic cancer, and EZH2 could be a potential therapeutic target for the treatment of pancreatic cancer. Although significant progress has been made toward understanding the function and deregulation of EZH2 in cancer cells, the posttranslational regulation of EZH2 in cancer cells is still unclear. F-box and WD repeat domain-containing 7 (FBW7) acts as a tumor suppressor by targeting multiple oncoprotein substrates for ubiquitination and degradation. Here we demonstrate that EZH2 is a bona fide substrate of FBW7 in pancreatic cancer cells. We provide evidence that the activated CDK5 kinase is involved in the EZH2 phosphorylation that is required for FBW7-mediated degradation. We further show that FBW7 suppresses EZH2 activity and inhibits tumor migration and invasion via degradation of EZH2 in pancreatic cancer cells. Furthermore, immunohistochemistry analysis revealed that expression of EZH2 protein negatively correlates with FBW7 protein levels in a cohort of human pancreatic cancer specimens. Collectively, our findings demonstrate that FBW7 is a novel E3 ligase of EZH2 that regulates the EZH2 protein level in pancreatic cancer and represents a viable strategy for effective treatment of pancreatic cancer.