title: 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: BACKGROUND
  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.
  
  
  CONCLUSIONS
  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.forename: Jun-Tang
authors.initials: JT
authors.lastname: Li
authors.forename: Li-Feng
authors.initials: LF
authors.lastname: Wang
authors.forename: Ya-Li
authors.initials: YL
authors.lastname: Zhao
authors.forename: Tao
authors.initials: T
authors.lastname: Yang
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.forename: Feng
authors.initials: F
authors.lastname: Yu
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.forename: Yan-Ling
authors.initials: YL
authors.lastname: Meng
authors.forename: Ning-Ning
authors.initials: NN
authors.lastname: Liu
authors.forename: Xiao-Shan
authors.initials: XS
authors.lastname: Zhu
authors.forename: Chun-Fang
authors.initials: CF
authors.lastname: Gao
authors.forename: Lin-Tao
authors.initials: LT
authors.lastname: Jia
authors.forename: An-Gang
authors.initials: AG
authors.lastname: Yang
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D061307:Human Umbilical Vein Endothelial Cells / Q000502:physiology; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000556:secondary; D008207:Lymphatic Metastasis; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D009368:Neoplasm Transplantation; D034622:RNA Interference; D062085:RNA, Long Noncoding / Q000235:genetics*; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics / Q000378:metabolism
chemical_list: C561566:HOTAIR long untranslated RNA, human; C587996:MIRN568 microRNA, human; D035683:MicroRNAs; C118125:NFAT5 protein, human; D062085:RNA, Long Noncoding; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; D014157:Transcription Factors; C467486:VEGFC protein, human; D042582:Vascular Endothelial Growth Factor C; C077591:S100A4 protein, human