Inhibition of BRD4 suppresses the malignancy of breast cancer cells via regulation of Snail

• Published in: Cell death and differentiation Vol. 27; no. 1; pp. 255 - 268
• Main Authors: Lu, Linlin, Chen, Zhuojia, Lin, Xinyao, Tian, Lin, Su, Qiao, An, Panpan, Li, Wuguo, Wu, Yingmin, Du, Jun, Shan, Hong, Chiang, Cheng-Ming, Wang, Hongsheng
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.01.2020; Nature Publishing Group UK
• Subjects: Animals; Antineoplastic Agents - therapeutic use; Azepines - therapeutic use; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Cycle Proteins - antagonists & inhibitors; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Line, Tumor; Cell Movement; Female; Gene Expression Regulation, Neoplastic; Humans; Kinases; Lung Neoplasms - drug therapy; Lung Neoplasms - secondary; Malignancy; Mice, Nude; Mice, SCID; Middle Aged; Proteasomes; Protein Kinase C - metabolism; Protein Stability; Proteins; Snail Family Transcription Factors - genetics; Snail Family Transcription Factors - metabolism; Snail Family Transcription Factors - physiology; Transcription Factors - antagonists & inhibitors; Transcription Factors - genetics; Transcription Factors - metabolism; Transcription, Genetic; Triazoles - therapeutic use; Xenografts; Zinc Finger Protein GLI1 - metabolism
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/s41418-019-0353-2

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.