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

Jian Shi; Yifan Wang; Lei Zeng; Yadi Wu; Jiong Deng; Qiang Zhang; Yiwei Lin; Junlin Li; Tiebang Kang; Min Tao; Elena Rusinova; Guangtao Zhang; Chi Wang; Haining Zhu; Jun Yao; Yi-Xin Zeng; B Mark Evers; Ming-Ming Zhou; Binhua P Zhou

doi:10.1016/j.ccr.2014.01.028

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

Cancer Cell. 2014 Feb 10;25(2):210-25. doi: 10.1016/j.ccr.2014.01.028.

Authors

Jian Shi¹, Yifan Wang², Lei Zeng³, Yadi Wu⁴, Jiong Deng⁵, Qiang Zhang³, Yiwei Lin¹, Junlin Li¹, Tiebang Kang⁶, Min Tao⁷, Elena Rusinova³, Guangtao Zhang³, Chi Wang⁸, Haining Zhu⁹, Jun Yao¹⁰, Yi-Xin Zeng⁶, B Mark Evers¹¹, Ming-Ming Zhou¹², Binhua P Zhou¹³

Affiliations

¹ 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.
² 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.
³ Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁴ 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.
⁵ 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.
⁶ Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, and Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060, China.
⁷ Department of Oncology, the First Affiliated Hospital of Soochow University, Suzhou 215006, China.
⁸ Markey Cancer Center, College of Medicine, University of Kentucky, Lexington, KY 40506, USA.
⁹ Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY 40506, USA.
¹⁰ Department of Molecular and Cellular Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
¹¹ 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.
¹² 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.
¹³ 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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Acetylation
Animals
Blotting, Western
Breast Neoplasms / genetics
Breast Neoplasms / pathology
Breast Neoplasms / prevention & control*
Carcinoma, Basal Cell / genetics
Carcinoma, Basal Cell / pathology
Carcinoma, Basal Cell / 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
Nuclear Proteins / chemistry
Nuclear Proteins / genetics
Nuclear Proteins / 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
Transcription Factors / genetics
Transcription Factors / metabolism*
Transcription, Genetic
Tumor Cells, Cultured
Twist-Related Protein 1 / antagonists & inhibitors
Twist-Related Protein 1 / metabolism*
Wnt Proteins / metabolism
Wnt-5a Protein

Substances

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

Associated data

GEO/GSE53222
PDB/2MJV

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding