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MicroRNA-455-3p mediates GATA3 tumor suppression in mammary epithelial cells by inhibiting TGF-β signaling.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2019 Oct 25; Vol. 294 (43), pp. 15808-15825. Date of Electronic Publication: 2019 Sep 06. - Publication Year :
- 2019
-
Abstract
- GATA3 is a basic and essential transcription factor that regulates many pathophysiological processes and is required for the development of mammary luminal epithelial cells. Loss-of-function GATA3 alterations in breast cancer are associated with poor prognosis. Here, we sought to understand the tumor-suppressive functions GATA3 normally performs. We discovered a role for GATA3 in suppressing epithelial-to-mesenchymal transition (EMT) in breast cancer by activating miR-455-3p expression. Enforced expression of miR-455-3p alone partially prevented EMT induced by transforming growth factor β (TGF-β) both in cells and tumor xenografts by directly inhibiting key components of TGF-β signaling. Pathway and biochemical analyses showed that one miRNA-455-3p target, the TGF-β-induced protein ZEB1, recruits the Mi-2/nucleosome remodeling and deacetylase (NuRD) complex to the promotor region of miR-455 to strictly repress the GATA3-induced transcription of this microRNA. Considering that ZEB1 enhances TGF-β signaling, we delineated a double-feedback interaction between ZEB1 and miR-455-3p, in addition to the repressive effect of miR-455-3p on TGF-β signaling. Our study revealed that a feedback loop between these two axes, specifically GATA3-induced miR-455-3p expression, could repress ZEB1 and its recruitment of NuRD (MTA1) to suppress miR-455, which ultimately regulates TGF-β signaling. In conclusion, we identified that miR-455-3p plays a pivotal role in inhibiting the EMT and TGF-β signaling pathway and maintaining cell differentiation. This forms the basis of that miR-455-3p might be a promising therapeutic intervention for breast cancer.<br /> (© 2019 Zeng et al.)
- Subjects :
- Animals
Base Sequence
Breast pathology
Breast Neoplasms genetics
Breast Neoplasms pathology
Cell Proliferation genetics
Epithelial-Mesenchymal Transition genetics
Estrogen Receptor alpha metabolism
Female
Gene Expression Regulation, Neoplastic
Humans
MCF-7 Cells
Mice, SCID
MicroRNAs genetics
Neoplasm Metastasis
Neoplasm Proteins metabolism
Transcription, Genetic
Zinc Finger E-box-Binding Homeobox 1 metabolism
Epithelial Cells metabolism
GATA3 Transcription Factor metabolism
MicroRNAs metabolism
Signal Transduction
Transforming Growth Factor beta metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 294
- Issue :
- 43
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 31492753
- Full Text :
- https://doi.org/10.1074/jbc.RA119.010800