1. Academic Validation
  2. MicroRNA-455-3p mediates GATA3 tumor suppression in mammary epithelial cells by inhibiting TGF-β signaling

MicroRNA-455-3p mediates GATA3 tumor suppression in mammary epithelial cells by inhibiting TGF-β signaling

  • J Biol Chem. 2019 Oct 25;294(43):15808-15825. doi: 10.1074/jbc.RA119.010800.
Yi Zeng 1 2 Tianyang Gao 1 Wei Huang 3 Yang Yang 1 Rongfang Qiu 1 Yongqiang Hou 1 Wenqian Yu 1 Shuai Leng 1 Dandan Feng 1 Wei Liu 1 Xu Teng 3 Hefen Yu 3 Yan Wang 4 3 5
Affiliations

Affiliations

  • 1 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
  • 2 Department of Biochemistry and Molecular Biology, Southwest Medical University, Luzhou, Sichuan 646000, China.
  • 3 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China.
  • 4 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China yanwang@tmu.edu.cn.
  • 5 State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
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.

Keywords

GATA transcription factor; GATA3; HDAC2; Smad2; ZEB1; breast cancer; epithelial-mesenchymal transition (EMT); gene regulation; miR-455-3p; microRNA (miRNA); nucleosome remodeling deacetylase (NuRD); transforming growth factor beta (TGF-beta).

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