Ko Hyeonseok, Kim Seongrak, Yang Kyungmi, Kim Kunhong
Laboratory of Molecular Oncology, Cheil General Hospital & Women's Healthcare Center, Dankook University College of Medicine, Jung-gu, Seoul, 04619, Korea.
Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Korea.
Oncogenesis. 2018 Mar 13;7(3):27. doi: 10.1038/s41389-018-0035-9.
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.
上皮-间质转化（EMT）是癌细胞侵袭和转移过程中的一个关键过程。E-钙黏蛋白向N-钙黏蛋白的转变被认为是EMT的分子标志。最近，我们报道CK2活性增加会完全诱导E-钙黏蛋白向N-钙黏蛋白的转变，但N-钙黏蛋白上调的分子机制尚不清楚。在本研究中，我们研究了CK2如何上调N-钙黏蛋白。N-钙黏蛋白启动子分析和染色质免疫沉淀分析鉴定并确认了髓系锌指1（MZF1）为N-钙黏蛋白转录因子。分子分析表明，MZF1直接与CK2相互作用，并在丝氨酸27处被磷酸化。磷酸化使MZF1稳定并诱导N-钙黏蛋白的转录。在表达N-钙黏蛋白的癌细胞中敲低MZF1（MKD）会下调N-钙黏蛋白的表达，并使细胞形态从纺锤形和成纤维细胞样恢复为圆形的上皮形状。此外，我们还表明，MKD降低了表达N-钙黏蛋白的癌细胞的运动性和侵袭性。总体而言，这些数据表明，在CK2介导的E-钙黏蛋白向N-钙黏蛋白转变过程中，N-钙黏蛋白的上调依赖于磷酸化介导的MZF1稳定。CK2可能是预防转移的一个良好治疗靶点。
