Journal
CELL DEATH AND DIFFERENTIATION
Volume 27, Issue 1, Pages 255-268Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41418-019-0353-2
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Funding
- National Natural Science Foundation of China [81673454, 81672608, 81472470]
- National Natural Science Foundation Key Project of China [81430041]
- Guangdong Natural Science Funds for Distinguished Young Scholar [2014A030306025]
- Guangdong Provincial Key Laboratory of Construction Foundation [2017B030314030]
- Guangdong Province Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation [2017B030314026]
- Fundamental Research Funds for the Central Universities (Sun Yat-sen University) [16ykpy09]
- US National Institutes of Health [CA103867]
- Cancer Prevention Research Institute of Texas [RP180349, RP190077]
- Welch Foundation [I-1805]
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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 Ser 11 of Snail and then inducing proteasome-mediated degradation. BRD4 inhibition also suppresses the expression of Glil, a key transductor of Hedgehog (Hh) required to activate the transcription of SNAIL, in BC cells. The GACCACC sequence (-341 to -333) in the SNAI1 promoter is responsible for Glil-induced transcription of SNAIl. 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.
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