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PMID: 24525235 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Disrupting the interaction of BRD4 with diacetylated Twist suppresses tumorigenesis in basal-like breast cancer.

Cancer cell ·Vol. 25 ·No. 2 ·2014-02-10 ·Pages 210-25

Shi J, Wang Y, Zeng L, Wu Y, Deng J, Zhang Q, Lin Y, Li J, Kang T, Tao M, Rusinova E, Zhang G, Wang C, Zhu H, Yao J, Zeng YX, Evers BM, Zhou MM, Zhou BP

Abstract

Twist is a key transcription activator of epithelial-mesenchymal transition (EMT). It remains unclear how Twist induces gene expression. Here we report a mechanism by which Twist recruits BRD4 to direct WNT5A expression in basal-like breast cancer (BLBC). Twist contains a "histone H4-mimic" GK-X-GK motif that is diacetylated by Tip60. The diacetylated Twist binds the second bromodomain of BRD4, whose first bromodomain interacts with acetylated H4, thereby constructing an activated Twist/BRD4/P-TEFb/RNA-Pol II complex at the WNT5A promoter and enhancer. Pharmacologic inhibition of the Twist-BRD4 association reduced WNT5A expression and suppressed invasion, cancer stem cell (CSC)-like properties, and tumorigenicity of BLBC cells. Our study indicates that the interaction with BRD4 is critical for the oncogenic function of Twist in BLBC.

MeSH Terms
Acetylation Animals Blotting, Western Breast Neoplasms/genetics,pathology,prevention & control Carcinoma, Basal Cell/genetics,pathology,prevention & control Cell Cycle Proteins Cell Transformation, Neoplastic Female Fluorescent Antibody Technique HeLa Cells Histone Acetyltransferases/metabolism Humans Immunoenzyme Techniques Lysine Acetyltransferase 5 Mice Mice, Inbred NOD Mice, SCID Neoplasm Invasiveness Neoplastic Stem Cells/pathology Nuclear Proteins/antagonists & inhibitors,chemistry,genetics,metabolism Positive Transcriptional Elongation Factor B/metabolism Promoter Regions, Genetic/genetics Proto-Oncogene Proteins/metabolism RNA Polymerase II/metabolism Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Transcription Factors/chemistry,genetics,metabolism Transcription, Genetic Tumor Cells, Cultured Twist-Related Protein 1/antagonists & inhibitors,metabolism Wnt Proteins/metabolism Wnt-5a Protein
Chemicals
BRD4 protein, human Cell Cycle Proteins Nuclear Proteins Proto-Oncogene Proteins TWIST1 protein, human Transcription Factors Twist-Related Protein 1 WNT5A protein, human Wnt Proteins Wnt-5a Protein Histone Acetyltransferases KAT5 protein, human Lysine Acetyltransferase 5 Positive Transcriptional Elongation Factor B RNA Polymerase II
Authors & Affiliations
19 authors, click to expand affiliations / ORCID
Shi Jian
Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY 40506, USA; Markey Cancer Center, College of Medicine, University of Kentucky, Lexington, KY 40506, USA.
Wang Yifan
Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY 40506, USA; Markey Cancer Center, College of Medicine, University of Kentucky, Lexington, KY 40506, USA; Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, and Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060, China.
Zeng Lei
Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Wu Yadi
Department of Molecular and Biomedical Pharmacology, College of Medicine, University of Kentucky, Lexington, KY 40506, USA; Markey Cancer Center, College of Medicine, University of Kentucky, Lexington, KY 40506, USA.
Deng Jiong
Department of Pathophysiology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, and Translation Medicine Center, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Zhang Qiang
Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Lin Yiwei
Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY 40506, USA; Markey Cancer Center, College of Medicine, University of Kentucky, Lexington, KY 40506, USA.
Li Junlin
Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY 40506, USA; Markey Cancer Center, College of Medicine, University of Kentucky, Lexington, KY 40506, USA.
Kang Tiebang
Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, and Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060, China.
Tao Min
Department of Oncology, the First Affiliated Hospital of Soochow University, Suzhou 215006, China.
Rusinova Elena
Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Zhang Guangtao
Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Wang Chi
Markey Cancer Center, College of Medicine, University of Kentucky, Lexington, KY 40506, USA.
Zhu Haining
Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY 40506, USA.
Yao Jun
Department of Molecular and Cellular Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Zeng Yi-Xin
Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, and Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060, China.
Evers B Mark
Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY 40506, USA; Department of Surgery, College of Medicine, University of Kentucky, Lexington, KY 40506, USA; Markey Cancer Center, College of Medicine, University of Kentucky, Lexington, KY 40506, USA.
Zhou Ming-Ming
Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: ming-ming.zhou@mssm.edu.
Zhou Binhua P
Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY 40506, USA; Markey Cancer Center, College of Medicine, University of Kentucky, Lexington, KY 40506, USA; Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, and Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060, China. Electronic address: peter.zhou@uky.edu.
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Article Info
Journal
Cancer cell
Abbr.
Cancer Cell
ISSN
1878-3686
DOI
10.1016/j.ccr.2014.01.028
Email
ming-ming.zhou@mssm.edu
peter.zhou@uky.edu
Published
2014-02-10
Pages
210-25
Language
English
Region
United States
NLM ID
101130617
PMCID
PMC4004960
Subset
IM
Grants
NCI NIH HHS · R01 CA125454 · United States
NCI NIH HHS · P30CA177558 · United States
NIGMS NIH HHS · P20 GM103486 · United States
NCI NIH HHS · R01 CA087658 · United States
NHGRI NIH HHS · HG004508 · United States
NIGMS NIH HHS · P20GM103486 · United States
NCI NIH HHS · P30 CA177558 · United States
NCI NIH HHS · P20CA153043 · United States
NHGRI NIH HHS · R01 HG004508 · United States
NCI NIH HHS · CA87658 · United States
NCI NIH HHS · CA125454 · United States
Databases
GEO
GSE53222
PDB
2MJV
External Links
PubMed source DOI: 10.1016/j.ccr.2014.01.028 PMC Full Text View journal details
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