Phosphorylation-dependent stabilization of MZF1 upregulates N-cadherin expression during protein kinase CK2-mediated epithelial-mesenchymal transition.
Phosphorylation-dependent stabilization of MZF1 upregulates N-cadherin expression during protein kinase CK2-mediated epithelial-mesenchymal transition.
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DOI：
10.1038/s41389-018-0035-9
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发表时间：
2018-03-13
期刊：
影响因子：
6.2
通讯作者：
Kim K
中科院分区：
文献类型：
--
作者：
Ko H;Kim S;Yang K;Kim K
上皮间质转化（EMT）是肿瘤细胞侵袭和转移的关键过程。E-cadherin到N-cadherin的转换被认为是EMT的分子标志。最近，我们报道了增加CK 2活性完全诱导E-cadherin向N-cadherin转换，但N-cadherin上调的分子机制尚不清楚。在这项研究中，我们研究了N-钙粘蛋白是如何上调CK 2。N-cadherin启动子分析和ChIP分析鉴定并确认髓样锌指1（MZF 1）为N-cadherin转录因子。分子分析表明，MZF 1直接与CK 2相互作用，并在丝氨酸27处磷酸化。磷酸化稳定MZF 1并诱导N-钙粘蛋白的转录。在表达N-钙粘蛋白的癌细胞中，MZF 1敲低（MKD）下调N-钙粘蛋白表达，并将形态从梭形和成纤维细胞样恢复为圆形上皮形状。此外，我们发现MKD降低了表达N-钙粘蛋白的癌细胞的运动性和侵袭性。总的来说，这些数据表明，N-钙粘蛋白上调CK 2介导的E-钙粘蛋白的N-钙粘蛋白开关依赖于磷酸化介导的MZF 1稳定。CK 2可能是一个很好的抗肿瘤转移的治疗靶点。
Epithelial-mesenchymal transition (EMT) is a critical process in invasion and metastasis of cancer cells. E-cadherin to N-cadherin switching is considered a molecular hallmark of EMT. Recently, we reported that increased CK2 activity fully induces E-cadherin to N-cadherin switching, but the molecular mechanisms of N-cadherin upregulation are unknown. In this study, we examined how N-cadherin is upregulated by CK2. N-cadherin promoter analysis and ChIP analysis identified and confirmed myeloid zinc finger 1 (MZF1) as an N-cadherin transcription factor. Molecular analysis showed that MZF1 directly interacts with CK2 and is phosphorylated at serine 27. Phosphorylation stabilizes MZF1 and induces transcription of N-cadherin. MZF1 knockdown (MKD) in N-cadherin-expressing cancer cells downregulates N-cadherin expression and reverts the morphology from spindle and fibroblast-like to a rounded, epithelial shape. In addition, we showed that that MKD reduced the motility and invasiveness of N-cadherin-expressing cancer cells. Collectively, these data indicate that N-cadherin upregulation in CK2-mediated E-cadherin to N-cadherin switching is dependent on phosphorylation-mediated MZF1 stabilization. CK2 could be a good therapeutic target for the prevention of metastasis.
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影响因子：
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