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

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

doi:10.1038/s41418-019-0353-2

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.

Highlights

Bromodomain-containing protein 4 (BRD4) is a member of the BET (Bromodomain and Extra-Terminal) family proteins [1]
Increased expression of BRD4 in breast cancer (BC) versus normal tissue has been observed in The Cancer Genome Atlas (TCGA), Crutis, and Finak data from Oncomine databases (Fig. 1b), suggesting BRD4 is generally upregulated in BC cells and tissues
We examined the biological effects of targeted inhibition of BRD4 on the development of BC

Summary

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Bromodomain-containing protein 4 (BRD4) is a member of the BET (Bromodomain and Extra-Terminal) family proteins [1]. It interacts primarily with acetylated histone H4 at. Recent studies revealed that BRD4 can regulate cell motility via regulating Jagged1/Notch signaling [10] and interacting with epithelial-mesenchymal transition (EMT) transcription factor (EMT-TF) Twist [11]. Considering that BRD4 function is highly context-dependent, we are interested in determining the roles of BRD4 and its regulatory effects on EMT-TFs and dissemination of breast cancer (BC) cells. Targeted inhibition of BRD4 suppressed EMT progression via protein kinase D1 (PRKD1)-mediated post-translational and Gli1-mediated transcriptional downregulation of Snail

Results

Discussion

Materials and methods

Compliance with ethical standards