Targeting the BRD4/FOXO3a/CDK6 axis sensitizes AKT inhibition in luminal breast cancer

• Published in: Nature communications Vol. 9; no. 1; pp. 5200 - 17
• Main Authors: Liu, Jingyi, Duan, Zhibing, Guo, Weijie, Zeng, Lei, Wu, Yadi, Chen, Yule, Tai, Fang, Wang, Yifan, Lin, Yiwei, Zhang, Qiang, He, Yanling, Deng, Jiong, Stewart, Rachel L., Wang, Chi, Lin, Pengnian Charles, Ghaffari, Saghi, Evers, B. Mark, Liu, Suling, Zhou, Ming-Ming, Zhou, Binhua P., Shi, Jian
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05.12.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13/51; 13/95; 14/63; 140/131; 38/39; 38/70; 42/89; 49/15; 49/91; 631/67; 631/67/1347; Acetylation; Acetylation - drug effects; AKT protein; Animals; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Cancer; Cell Cycle Proteins; Cell Line, Tumor; Cell Nucleus - genetics; Cell Nucleus - metabolism; Cyclin-dependent kinase 6; Cyclin-Dependent Kinase 6 - genetics; Cyclin-Dependent Kinase 6 - metabolism; Dephosphorylation; Drug resistance; Female; Forkhead Box Protein O3 - genetics; Forkhead Box Protein O3 - metabolism; FOXO3 protein; Gene expression; Gene Expression Regulation; Heterocyclic Compounds, 3-Ring - administration & dosage; Humanities and Social Sciences; Humans; In vivo methods and tests; Inhibitors; Mice; Mice, Nude; multidisciplinary; Nuclear Proteins - chemistry; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Nuclear transport; Oxadiazoles - administration & dosage; Pharmacology; Promoter Regions, Genetic; Protein Binding - drug effects; Protein Domains; Protein Kinase Inhibitors - administration & dosage; Protein Transport - drug effects; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Pyrimidines - administration & dosage; Pyrroles - administration & dosage; Science; Science (multidisciplinary); Sirtuins - genetics; Sirtuins - metabolism; Transcription; Transcription Factors - chemistry; Transcription Factors - genetics; Transcription Factors - metabolism; Translocation; Tumor cells

BRD4 assembles transcriptional machinery at gene super-enhancer regions and governs the expression of genes that are critical for cancer progression. However, it remains unclear whether BRD4-mediated gene transcription is required for tumor cells to develop drug resistance. Our data show that prolon...