Dysfunction of the Reciprocal Feedback Loop between GATA3- and ZEB2-Nucleated Repression Programs Contributes to Breast Cancer Metastasis

Cancer Cell. 2015 Jun 8;27(6):822-36. doi: 10.1016/j.ccell.2015.04.011.

Wenzhe Si ¹, Wei Huang ², Yu Zheng ², Yang Yang ², Xujun Liu ¹, Lin Shan ², Xing Zhou ², Yue Wang ², Dongxue Su ², Jie Gao ², Ruorong Yan ¹, Xiao Han ¹, Wanjin Li ¹, Lin He ¹, Lei Shi ², Chenghao Xuan ², Jing Liang ¹, Luyang Sun ¹, Yan Wang ³, Yongfeng Shang ⁴

Affiliations

1 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China.
2 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, Department of Biochemistry and Molecular Biology, Tianjin Medical University, Tianjin 300070, China.
3 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, Department of Biochemistry and Molecular Biology, Tianjin Medical University, Tianjin 300070, China. Electronic address: yanwang@tmu.edu.cn.
4 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China; 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, Department of Biochemistry and Molecular Biology, Tianjin Medical University, Tianjin 300070, China. Electronic address: yshang@hsc.pku.edu.cn.

PMID: 26028330 DOI: 10.1016/j.ccell.2015.04.011

Abstract

How loss-of-function of GATA3 contributes to the development of breast Cancer is poorly understood. Here, we report that GATA3 nucleates a transcription repression program composed of G9A and MTA3-, but not MTA1- or MTA2-, constituted NuRD complex. Genome-wide analysis of the GATA3/G9A/NuRD(MTA3) targets identified a cohort of genes including ZEB2 that are critically involved in epithelial-to-mesenchymal transition and cell invasion. We demonstrate that the GATA3/G9A/NuRD(MTA3) complex inhibits the invasive potential of breast Cancer cells in vitro and suppresses breast Cancer metastasis in vivo. Strikingly, the expression of GATA3, G9A, and MTA3 is concurrently downregulated during breast Cancer progression, leading to an elevated expression of ZEB2, which, in turn, represses the expression of G9A and MTA3 through the recruitment of G9A/NuRD(MTA1).

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