KRAB zinc-finger protein 382 regulates epithelial-mesenchymal transition and functions as a tumor suppressor, but is silenced by CpG methylation in gastric cancer

Abstract Background Zinc-finger protein 471 (ZNF471) is a member of the Krüppel-associated box domain zinc finger protein (KRAB-ZFP) family. ZNF471 is methylated in squamous cell carcinomas of tongue, stomach and esophageal. However, its role in breast carcinogenesis remains elusive. Here, we studied its expression, functions, and molecular mechanisms in breast cancer. Methods We examined ZNF471 expression by RT-PCR and qPCR. Methylation-specific PCR determined its promoter methylation. Its biological functions and related molecular mechanisms were assessed by CCK-8, clonogenicity, wound healing, Transwell, nude mice tumorigenicity, flow cytometry, BrdU-ELISA, immunohistochemistry and Western blot assays. Results ZNF471 was significantly downregulated in breast cell lines and tissues due to its promoter CpG methylation, compared with normal mammary epithelial cells and paired surgical-margin tissues. Ectopic expression of ZNF471 substantially inhibited breast tumor cell growth in vitro and in vivo, arrested cell cycle at S phase, and promoted cell apoptosis, as well as suppressed metastasis. Further knockdown of ZNF471 verified its tumor-suppressive effects. We also found that ZNF471 exerted its tumor-suppressive functions through suppressing epithelial-mesenchymal transition, tumor cell stemness and AKT and Wnt/β-catenin signaling. Conclusions ZNF471 functions as a tumor suppressor that was epigenetically inactivated in breast cancer. Its inhibition of AKT and Wnt/β-catenin signaling pathways is one of the mechanisms underlying its anti-cancer effects.

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56 Zinc Finger Protein 545 is a Functional Tumor Suppressor Through Inhibiting Ribosomal RNA Transcription in Gastric Cancer

Gastroenterology ◽

10.1016/s0016-5085(12)60056-0 ◽

2012 ◽

Vol 142 (5) ◽

pp. S-15

Author(s):

Shiyan Wang ◽

Wan Du ◽

Xiaoxing Li ◽

Qian Tao ◽

Joseph J. Sung ◽

...

Keyword(s):

Gastric Cancer ◽

Tumor Suppressor ◽

Zinc Finger ◽

Ribosomal Rna ◽

Zinc Finger Protein ◽

Rna Transcription ◽

Finger Protein

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The Zinc-Finger Protein Slug Causes Desmosome Dissociation, an Initial and Necessary Step for Growth Factor–induced Epithelial–Mesenchymal Transition

The Journal of Cell Biology ◽

10.1083/jcb.137.6.1403 ◽

1997 ◽

Vol 137 (6) ◽

pp. 1403-1419 ◽

Cited By ~ 343

Author(s):

Pierre Savagner ◽

Kenneth M. Yamada ◽

Jean Paul Thiery

Keyword(s):

Growth Factor ◽

Zinc Finger ◽

Cell Separation ◽

Zinc Finger Protein ◽

Epithelial Mesenchymal Transition ◽

Cell Spreading ◽

Cell Contact ◽

Mesenchymal Transition ◽

Finger Protein ◽

Cell Cell

Epithelial–mesenchymal transition (EMT) is an essential morphogenetic process during embryonic development. It can be induced in vitro by hepatocyte growth factor/scatter factor (HGF/SF), or by FGF-1 in our NBT-II cell model for EMT. We tested for a central role in EMT of a zinc-finger protein called Slug. Slug mRNA and protein levels were increased transiently in FGF-1–treated NBT-II cells. Transient or stable transfection of Slug cDNA in NBT-II cells resulted in a striking disappearance of the desmosomal markers desmoplakin and desmoglein from cell–cell contact areas, mimicking the initial steps of FGF-1 or HGF/SF- induced EMT. Stable transfectant cells expressed Slug protein and were less epithelial, with increased cell spreading and cell–cell separation in subconfluent cultures. Interestingly, NBT-II cells transfected with antisense Slug cDNA were able to resist EMT induction by FGF-1 or even HGF/SF. This antisense effect was suppressed by retransfection with Slug sense cDNA. Our results indicate that Slug induces the first phase of growth factor–induced EMT, including desmosome dissociation, cell spreading, and initiation of cell separation. Moreover, the antisense inhibition experiments suggest that Slug is also necessary for EMT.

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