Oncotarget

Research Papers:

ZEB1 confers stem cell-like properties in breast cancer by targeting neurogenin-3

Chen Zhou, Huimin Jiang, Zhen Zhang, Guomin Zhang, Hang Wang, Quansheng Zhang, Peiqing Sun, Rong Xiang and Shuang Yang _

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Oncotarget. 2017; 8:54388-54401. https://doi.org/10.18632/oncotarget.17077

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Abstract

Chen Zhou1,*, Huimin Jiang1,*, Zhen Zhang1, Guomin Zhang1, Hang Wang1, Quansheng Zhang2, Peiqing Sun3, Rong Xiang1 and Shuang Yang1

1Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, Medical School of Nankai University, Tianjin 300071, China

2Tianjin Key Laboratory of Organ Transplantation, Tianjin First Center Hospital, Tianjin 300192, China

3Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA

*These authors have contributed equally to this work

Correspondence to:

Shuang Yang, email: [email protected]

Keywords: breast cancer, neurogenin-3, stemness properties, tumor initiation, ZEB1

Received: December 29, 2016     Accepted: March 20, 2017     Published: April 13, 2017

ABSTRACT

Cancer stem cells (CSCs) are a subpopulation of cancer cells believed to be implicated in cancer initiation, progression, and recurrence. Here, we report that ectopic expression of zinc finger E-box binding homeobox 1 protein (ZEB1) results in the acquisition of CSC properties by breast cancer cells, leading to tumor initiation and progression in vitro and in vivo. The neurogenin 3 gene (Ngn3) is a bona fide target of ZEB1, and its repression is a key factor contributing to ZEB1-induced cancer cell stemness. ZEB1 suppressed Ngn3 transcription by forming a ZEB1/DNA methyltransferase (DNMT)3B/histone deacetylase 1 (HDAC1) complex on the Ngn3 promoter, leading to promoter hypermethylation and gene silencing. The rescue of Ngn3 expression attenuated ZEB1-induced cancer stemness and symmetric CSC division. Immunohistological analysis of human breast cancer specimens revealed a strong inverse relationship between ZEB1 and NGN3 protein expression. Thus, our findings suggest ZEB1-mediated silencing of Ngn3 is required for breast tumor initiation and maintenance. Targeted therapies against the ZEB1/Ngn3 axis may be highly valuable for the prevention and treatment of breast cancer.


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