DEDD Interacts with PI3KC3 to Activate Autophagy and Attenuate Epithelial-Mesenchymal Transition in Human Breast Cancer
DEDD Interacts with PI3KC3 to Activate Autophagy and Attenuate Epithelial-Mesenchymal Transition in Human Breast Cancer
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DOI：
10.1158/0008-5472.can-11-3832
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发表时间：
2012-07-01
期刊：
影响因子：
11.2
通讯作者：
Hu, Zhuo-Wei
中科院分区：
文献类型：
--
作者：
Lv, Qi;Wang, Wei;Hu, Zhuo-Wei
上皮间质转化（EMT）是一个重要的发育过程，有助于癌症侵袭和转移。在这项研究中，我们发现含有死亡效应结构域的 DNA 结合蛋白 (DEDD) 会减弱 EMT，并充当肿瘤生长和转移的内源性抑制剂。我们发现 DEDD 的表达水平与乳腺癌和结肠癌患者的不良预后呈负相关。在体外和体内，DEDD的过度表达减弱了高度转移细胞的侵袭表型，而DEDD的沉默促进了非转移细胞的侵袭。通过与 III 类 PI-3 激酶 (PI3KC3)/Beclin1 直接相互作用，DEDD 激活自噬并诱导 Snail 和 Twist（EMT 的两个主要调节因子）的降解。 DEDD-PI3KC3 相互作用导致 PI3KC3 稳定，进一步促进自噬以及 Snail 和 Twist 的降解。总之，我们的研究结果强调了细胞内信号蛋白 DEDD 作为内源性肿瘤抑制因子发挥作用的新机制。因此，DEDD 表达可能代表预防和治疗癌症转移的预后标志物和潜在治疗靶点。癌症研究； 72(13)； 3238-50。 (c) 2012 年 AACR。
Epithelial-to-mesenchymal transition (EMT), a crucial developmental program, contributes to cancer invasion and metastasis. In this study, we show that death-effector domain-containing DNA-binding protein (DEDD) attenuates EMT and acts as an endogenous suppressor of tumor growth and metastasis. We found that expression levels of DEDD were conversely correlated with poor prognosis in patients with breast and colon cancer. Both in vitro and in vivo, overexpression of DEDD attenuated the invasive phenotype of highly metastatic cells, whereas silencing of DEDD promoted the invasion of nonmetastatic cells. Via direct interaction with the class III PI-3-kinase (PI3KC3)/Beclin1, DEDD activated autophagy and induced the degradation of Snail and Twist, two master regulators of EMT. The DEDD-PI3KC3 interaction led to stabilization of PI3KC3, which further contributed to autophagy and the degradation of Snail and Twist. Together, our findings highlight a novel mechanism in which the intracellular signaling protein DEDD functions as an endogenous tumor suppressor. DEDD expression therefore may represent a prognostic marker and potential therapeutic target for the prevention and treatment of cancer metastasis. Cancer Res; 72(13); 3238-50. (c) 2012 AACR.