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 prolonged treatment of luminal breast cancer cells with AKT inhibitors induces FOXO3a dephosphorylation, nuclear translocation, and disrupts its association with SirT6, eventually leading to FOXO3a acetylation as well as BRD4 recognition. Acetylated FOXO3a recognizes the BD2 domain of BRD4, recruits the BRD4/RNAPII complex to the CDK6 gene promoter, and induces its transcription. Pharmacological inhibition of either BRD4/FOXO3a association or CDK6 significantly overcomes the resistance of luminal breast cancer cells to AKT inhibitors in vitro and in vivo. Our study reports the involvement of BRD4/FOXO3a/CDK6 axis in AKTi resistance and provides potential therapeutic strategies for treating resistant breast cancer.
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This research was supported by the Shared Resources of the University of Kentucky Markey Cancer Center (P30CA177558) and University of Kentucky Center of Biomedical Research Excellence in Cancer and Metabolism (P20 GM121327). This work was also supported by grants from NIH (CA125454 and CA188118 to B.P.Z., and CA87658 and CA203067 to M.M.Z.), and DoD (BC140733 to M.M.Z. and B.P.Z.). This work was also supported in part by National Natural Science Foundation of China (81672629 to J.S.; 81402434 to Y.W.; 81530075 and 81773155 to S.L.), Science and Technology Program of Guangzhou, China (201707010331 to J.S.), and Basic Public Welfare Research Program of Zhejiang Province (LGF18H290003 to Y.W.).
RNA-sequencing data are available at the GEO data repository with the accession code GSE118148. The solution structure of the BRD4-BD2 in complex with Foxo3a-K242ac/K245ac peptide and the NMR spectral data are deposited in Protein Data Bank (PDB) ID 6MNL and BioMagResBank (BMRB) ID 30373, respectively. All uncropped western blot images were presented in Supplementary Figure 6. All tumor images and source data of this study are available upon request.
Supplementary Information accompanies this paper at https://doi.org/10.1038/s41467-018-07258-y.
Liu, Jingyi; Guo, Weijie; Duan, Zhibing; 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.; and Shi, Jian, "Targeting the BRD4/FOXO3a/CDK6 Axis Sensitizes AKT Inhibition in Luminal Breast Cancer" (2018). Molecular and Cellular Biochemistry Faculty Publications. 151.