Inhibition of BRD4 suppresses the malignancy of breast cancer cells via regulation of Snail
Authors: Cheng-Ming Chiang
Xinyao Lin
Qiao Su
Hong Shan
Zhuojia Chen
Lin Tian
Panpan An
Yingmin Wu
Wuguo Li
Linlin Lu
Jun Du
Hongsheng Wang
Journal: Cell death and differentiation (2020)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: BRD4; cancer motility; epithelial-mesenchymal transition (EMT); migration; invasion
Affiliations: Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong, 510006, China., Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, 510060, China., Department of Pharmacy, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, 519000, China., Laboratory Animal Center, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, 510080, China., Key Laboratory of Biomedical Imaging of Guangdong Province, Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, 519000, China., Simmons Comprehensive Cancer Center, Department of Pharmacology, and Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA. ., Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong, 510006, China. .

Abstract:  The mechanistic action of bromodomain-containing protein 4 (BRD4) in cancer motility, including epithelial-mesenchymal transition (EMT), remains largely undefined. We found that targeted inhibition of BRD4 reduces migration, invasion, in vivo growth of patient-derived xenograft (PDX), and lung colonization of breast cancer (BC) cells. Inhibition of BRD4 rapidly decreases the expression of Snail, a powerful EMT transcription factor (EMT-TF), via diminishing its protein stability and transcription. Protein kinase D1 (PRKD1) is responsible for BRD4-regulated Snail protein stability by triggering phosphorylation at Ser11 of Snail and then inducing proteasome-mediated degradation. BRD4 inhibition also suppresses the expression of Gli1, a key transductor of Hedgehog (Hh) required to activate the transcription of SNAI1, in BC cells. The GACCACC sequence (-341 to -333) in the SNAI1 promoter is responsible for Gli1-induced transcription of SNAI1. Clinically, BRD4 and Snail levels are increased in lung-metastasized, estrogen receptor-negative (ER-), and progesterone receptor-negative (PR-) breast cancers and correlate with the expression of mesenchymal markers. Collectively, BRD4 can regulate malignancy of breast cancer cells via both transcriptional and post-translational regulation of Snail. 

Retracted: No

PubPeer comments:
 The authors may check the problems of indicated bands in Fig. 3D and Fig. 1G. ![file] , 
 I was unaware of this. Thanks for pointing this out. I ll communicate with the lead PI for his clarification. , 
 Dear Dr Stegnus, Thank you for your interest in our research and your efforts to ensure the accuracy of scientific research. Regarding your comments on Fig. 3 D and Fig. 1 G. The GAPDH images are identical between two figures. The FN and Snail seems different. I thought the student may use one batch samples to test the expression of FN, Snail and others via using several different gels or one gel and then cut to several bands according to the molecular weight, and then use the same GAPDH for that batch of samples. I checked back to studentu2019s lab meeting reports, actually we have done several times of these two experiments. The conclusion is credible. Now I am asking another student to repeat it and will contact the editor of the journal to resubmit the repeated data. Best Regards. Hongsheng Wang ,