RETRACTED ARTICLE: Nuclear factor of activated T cells 5 maintained by Hotair suppression of miR-568 upregulates S100 calcium binding protein A4 to promote breast cancer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

IntroductionThe 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.MethodsThe 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.ResultsIn 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.ConclusionThis 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-014-0454-2) contains supplementary material, which is available to authorized users.

LncRNA HOTAIR: A master regulator of chromatin dynamics and cancer

“…Treatment of calycosin or genistein also decreased phosphorylation of Akt, and also the expression of its downstream target, HOTAIR [126]. Mechanistic studies show that HOTAIR suppress a miRNA (miR-568) and in turn augments the NFAT5 (Nuclear factor of activated T cells 5) expression in metastatic breast cancers [127]. Another study showed that downregulation of miR-7 in breast cancer stem cells may be indirectly attributed to HOTAIR by modulating the expression of HOXD10 that promotes the expression of miR-7.…”

LncRNAs: From Basic Research to Medical Application

“…Li JT. et al, identified that HOTAIR could suppress the miR-568 to up-regulate the expression of S100 calcium binding protein A1 (S100A), and then facilitates the metastasis of breast cancer 45. The B-Raf proto-oncogene, serine/threonine kinase (BRAF) pseudogene 1 is a newly reported lncRNA that functions as a ceRNA for BRAF, in part by sponging miR-30a, miR-182, and miR-87646.…”

“…Dextran nanoparticles can deliver chemotherapy to the nucleus, which may be used to attach cytotoxic agents to lncRNAs 66. The plasmid DTA-H19 was designed to express a diphtheria toxin subunit controlled by the H19 promoter 72, 73, which could be injected into tumor and lead to a H19-dependent activation of diphtheria toxin within the tumor 45. Another emerging method is to increase the activity of tumor suppressor by neutralizing the inhibitory effects of lncRNAs through antisense oligo nucleotides 66.…”

Control of cell mechanics by RhoA and calcium fluxes during epithelial scattering

“…113,117 S100A4 is upregulated by canonical Wnt signaling, and inhibition of b-catenin decreases tumor cell migration and invasion through downregulation of S100A4. 106,109 NFAT is expressed in metastatic breast cancer and also transcriptionally activates S100A4, 118 Interestingly, NFAT activation is driven by calcium influxes during epithelial scattering of MDCK cells, 31 indicating that there might be multiple connections between S100A4 and increased intracellular calcium concentration in EMT.…”