CUL4A induces epithelial-mesenchymal transition and promotes cancer metastasis by regulating ZEB1 expression.
CUL4A induces epithelial-mesenchymal transition and promotes cancer metastasis by regulating ZEB1 expression.
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DOI：
10.1158/0008-5472.can-13-2182
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发表时间：
2014-01-15
期刊：
影响因子：
11.2
通讯作者：
Wei G
中科院分区：
文献类型：
--
作者：
Wang Y;Wen M;Kwon Y;Xu Y;Liu Y;Zhang P;He X;Wang Q;Huang Y;Jen KY;LaBarge MA;You L;Kogan SC;Gray JW;Mao JH;Wei G
泛素连接酶CUL 4A与肿瘤发生有关，但其对肿瘤进展和转移的作用尚未得到评价。在这里，我们发现CUL 4A在乳腺癌以及卵巢癌、胃癌和结直肠癌中升高，其表达水平与远处转移呈正相关。CUL 4A在正常或恶性人乳腺上皮细胞中的过表达增加了它们在体外和体内的肿瘤性质，显著增加了上皮-间质转化（EMT）和恶性细胞的转移能力。相反，在侵袭性乳腺癌细胞中沉默CUL 4A抑制了这些过程。从机制上讲，我们发现CUL 4A在EMT调控基因ZEB 1的启动子处以与其转录相关的方式调节组蛋白H3 K4 me 3。ZEB 1沉默阻断CUL 4A驱动的增殖、EMT、肿瘤发生和转移。此外，在人乳腺癌中，ZEB 1表达与CUL 4A表达和远处转移呈正相关。综上所述，我们的研究结果揭示了CUL 4A在调节乳腺癌细胞转移行为中的关键作用。
The ubiquitin ligase CUL4A has been implicated in tumorigenesis but its contributions to progression and metastasis have not been evaluated. Here we show that CUL4A is elevated in breast cancer as well as ovarian, gastric and colorectal tumors where its expression level correlates positively with distant metastasis. CUL4A overexpression in normal or malignant human mammary epithelial cells increased their neoplastic properties in vitro and in vivo, markedly increasing epithelial-mesenchymal transition (EMT) and the metastatic capacity of malignant cells. In contrast, silencing CUL4A in aggressive breast cancer cells inhibited these processes. Mechanistically, we found CUL4A modulated histone H3K4me3 at the promoter of the EMT regulatory gene ZEB1 in a manner associated with its transcription. ZEB1 silencing blocked CUL4A-driven proliferation, EMT, tumorigenesis and metastasis. Further, in human breast cancers ZEB1 expression correlated positively with CUL4A expression and distant metastasis. Taken together, our findings reveal a pivotal role of CUL4A in regulating the metastatic behavior of breast cancer cells.