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.
Highlights
GATA3 is a basic and essential transcription factor that regulates many pathophysiological processes and is required for the development of mammary luminal epithelial cells
We have previously shown that GATA3 coordinates a program of transcriptional repression composed of G9A and the MTA3-Mi-2/ nucleosome remodeling and deacetylase (NuRD)2 complex, which represses a cohort of genes including ZEB2 and inhibits the invasive potential and metastasis of breast cancer [7]
We found that MCF-7 cells with GATA3 depletion underwent epithelial-to-mesenchymal transition (EMT), as indicated by the loss of ␣-catenin and E-cadherin and the up-regulation of N-cadherin and fibronectin (Fig. 1A, right)
Summary
NuRD, nucleosome remodeling and deacetylase; miRNA, microRNA; TGF-, transforming growth factor-; EMT, epithelial-to-mesenchymal transition; qPCR, quantitative PCR; ER, estrogen receptor; qChIP, quantitative ChIP; SCID, severe combined immunodeficiency; GSEA, Gene Set Enrichment Analysis; MTA, metastasis-associated; EdU, 5-ethynyl-2Ј-deoxyuridine; GST, glutathione S-transferase; DAPI, 4Ј,6-diamidino-2-phenylindole. GATA3 regulates miR-455-3p to inhibit TGF- signaling lated and activated Smad and Smad form a complex with Smad to promote the expression of the three families of EMTinducing transcription factors, namely Snail/Slug, ZEB1/2, and Twist [15, 17, 18]. These transcription factors, which have historically been implicated in lineage determination, repress the expression of epithelial markers while activating the expression of mesenchymal markers [18]. We explored the molecular mechanism underlying the functional interplay among miR-455-3p, Smad, ZEB1, and HDAC2 to investigate the role of miR-455-3p in EMT and breast cancer progression
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