title: Disrupting the interaction of BRD4 with diacetylated Twist suppresses tumorigenesis in basal-like breast cancer.
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.
authors: 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.
authors: Jian
authors: J
authors: Shi
authors: 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.
authors: Yifan
authors: Y
authors: Wang
authors: Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Lei
authors: L
authors: Zeng
authors: 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.
authors: Yadi
authors: Y
authors: Wu
authors: 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.
authors: Jiong
authors: J
authors: Deng
authors: Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Qiang
authors: Q
authors: Zhang
authors: 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.
authors: Yiwei
authors: Y
authors: Lin
authors: 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.
authors: Junlin
authors: J
authors: Li
authors: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, and Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060, China.
authors: Tiebang
authors: T
authors: Kang
authors: Department of Oncology, the First Affiliated Hospital of Soochow University, Suzhou 215006, China.
authors: Min
authors: M
authors: Tao
authors: Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Elena
authors: E
authors: Rusinova
authors: Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Guangtao
authors: G
authors: Zhang
authors: Markey Cancer Center, College of Medicine, University of Kentucky, Lexington, KY 40506, USA.
authors: Chi
authors: C
authors: Wang
authors: Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY 40506, USA.
authors: Haining
authors: H
authors: Zhu
authors: Department of Molecular and Cellular Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors: Jun
authors: J
authors: Yao
authors: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, and Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060, China.
authors: Yi-Xin
authors: YX
authors: Zeng
authors: 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.
authors: B Mark
authors: BM
authors: Evers
authors: 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.
authors: Ming-Ming
authors: MM
authors: Zhou
authors: 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.
authors: Binhua P
authors: BP
authors: Zhou
mesh_terms: D000107:Acetylation; D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D002280:Basal Cell Carcinoma / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D018797:Cell Cycle Proteins; D002471:Cell Transformation, Neoplastic; D005260:Female; D005455:Fluorescent Antibody Technique; D006367:HeLa Cells; D051548:Histone Acetyltransferases / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D000074443:Lysine Acetyltransferase 5; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000473:pathology*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D042925:Positive Transcriptional Elongation Factor B / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D012319:RNA Polymerase II / Q000378:metabolism*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D051879:Twist-Related Protein 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism; D000071818:Wnt-5a Protein; D000092468:Bromodomain Containing Proteins
chemical_list: D018797:Cell Cycle Proteins; D051548:Histone Acetyltransferases; D000074443:Lysine Acetyltransferase 5; D009687:Nuclear Proteins; D042925:Positive Transcriptional Elongation Factor B; D011518:Proto-Oncogene Proteins; D012319:RNA Polymerase II; D014157:Transcription Factors; D051879:Twist-Related Protein 1; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C103173:TWIST1 protein, human; C085389:WNT5A protein, human; C098489:KAT5 protein, human