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

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

doi:10.1016/j.ccell.2015.04.011

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. Epub 2015 May 28.

Authors

Wenzhe Si¹, Wei Huang², Yu Zheng², Yang Yang², Xujun Liu¹, Lin Shan², Xing Zhou², Yue Wang², Dongxue Su², Jie Gao², Ruorong Yan¹, Xiao Han¹, Wanjin Li¹, Lin He¹, Lei Shi², Chenghao Xuan², Jing Liang¹, Luyang Sun¹, Yan Wang³, Yongfeng Shang⁴

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).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Breast Neoplasms / genetics
Breast Neoplasms / metabolism*
Breast Neoplasms / pathology*
Epithelial-Mesenchymal Transition
Female
GATA3 Transcription Factor / genetics
GATA3 Transcription Factor / metabolism*
Heterografts
Homeodomain Proteins / genetics
Homeodomain Proteins / metabolism*
Humans
MCF-7 Cells
Mice
Mice, Nude
Mice, SCID
Neoplasm Metastasis
Repressor Proteins / genetics
Repressor Proteins / metabolism*
Transfection
Zinc Finger E-box Binding Homeobox 2

Substances

GATA3 Transcription Factor
GATA3 protein, human
Homeodomain Proteins
Repressor Proteins
ZEB2 protein, human
Zinc Finger E-box Binding Homeobox 2

Associated data

GEO/GSE67206