Nuclear factor of activated T cells 5 maintained by Hotair suppression of miR-568 upregulates S100 calcium binding protein A4 to promote breast cancer metastasis.

Abstract

INTRODUCTION:

The onset of distal metastasis, which underlies the high mortality of breast cancers, warrants substantial studies to depict its molecular basis. Nuclear factor of activated T cells 5 (NFAT5) is upregulated in various malignancies and is critically involved in migration and invasion of neoplastic cells. Nevertheless, the metastasis-related events potentiated by this transcriptional factor and the mechanism responsible for NFAT5 elevation in carcinoma cells remain to be fully elucidated.

METHODS:

The correlation of NFAT5 with breast cancer invasiveness was investigated in vitro and clinically. The genes transcriptionally activated by NFAT5 were probed and their roles in breast cancer progression were dissected. The upstream regulators of NFAT5 were studied with particular attempt to explore the involvement of non-coding RNAs, and the mechanism underlying the maintenance of NFAT5 expression was deciphered.

RESULTS:

In metastatic breast cancers, NFAT5 promotes epithelial-mesenchymal transition (EMT) and invasion of cells by switching on the expression of the calcium binding protein S100A4, and facilitates the angiogenesis of breast epithelial cells and thus the development of metastases by transcriptionally activating vascular endothelial growth factor C (VEGF-C). NFAT5 is directly targeted by miR-568, which is in turn suppressed by the long non-coding RNA, Hotair, via a documented in trans gene silencing pattern, that is recruitment of the polycomb complex (Polycomb Repressive Complex 2; PRC2) and LSD1, and consequently methylation of histone H3K27 and demethylation of H3K4 on the miR-568 loci.

CONCLUSION:

This study unravels a detailed role of NFAT5 in mediating metastatic signaling, and provides broad insights into the involvement of Hotair, in particular, by transcriptionally regulating the expression of microRNA(s), in the metastasis of breast cancers.

• Authors: Jun-Tang Li, Li-Feng Wang, Ya-Li Zhao, Tao Yang, Wei Li, Jing Zhao, Feng Yu, Lei Wang, Yan-Ling Meng, Ning-Ning Liu, Xiao-Shan Zhu, Chun-Fang Gao, Lin-Tao Jia, An-Gang Yang
• Journal: Breast cancer research : BCR (Breast Cancer Res) Vol. 16 Issue 5 Pg. 454 (Oct 14 2014) ISSN: 1465-542X [Electronic] England
• PMID: 25311085 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Retracted Publication)

Chemical References

• HOTAIR long untranslated RNA, human
• MIRN568 microRNA, human
• MicroRNAs
• NFAT5 protein, human
• RNA, Long Noncoding
• S100 Calcium-Binding Protein A4
• S100 Proteins
• Transcription Factors
• VEGFC protein, human
• Vascular Endothelial Growth Factor C
• S100A4 protein, human

Topics

• Animals
• Base Sequence
• Binding Sites
• Breast Neoplasms (genetics, metabolism, pathology)
• Cell Line, Tumor
• Epithelial-Mesenchymal Transition
• Female
• Gene Expression Regulation, Neoplastic
• Human Umbilical Vein Endothelial Cells (physiology)
• Humans
• Lung Neoplasms (genetics, metabolism, secondary)
• Lymphatic Metastasis
• Mice, Inbred BALB C
• Mice, Nude
• MicroRNAs (genetics)
• Neoplasm Transplantation
• RNA Interference
• RNA, Long Noncoding (genetics)
• S100 Calcium-Binding Protein A4
• S100 Proteins (genetics, metabolism)
• Transcription Factors (genetics, metabolism)
• Up-Regulation
• Vascular Endothelial Growth Factor C (genetics, metabolism)