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

Linlin Lu, Zhuojia Chen, Xinyao Lin, Lin Tian, Qiao Su, Panpan An, Wuguo Li, Yingmin Wu, Jun Du, Hong Shan, Cheng Ming Chiang, Hongsheng Wang

Research output: Contribution to journalArticle

6 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)255-268
Number of pages14
JournalCell Death and Differentiation
Volume27
Issue number1
DOIs
StatePublished - Jan 1 2020

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Inhibition of BRD4 suppresses the malignancy of breast cancer cells via regulation of Snail'. Together they form a unique fingerprint.

  • Cite this

    Lu, L., Chen, Z., Lin, X., Tian, L., Su, Q., An, P., Li, W., Wu, Y., Du, J., Shan, H., Chiang, C. M., & Wang, H. (2020). Inhibition of BRD4 suppresses the malignancy of breast cancer cells via regulation of Snail. Cell Death and Differentiation, 27(1), 255-268. https://doi.org/10.1038/s41418-019-0353-2