AI Article Synopsis
- BRD4 is important for regulating gene expression at super-enhancer regions, which affects cancer progression, but its role in drug resistance is not fully understood.
- Treatment with AKT inhibitors in luminal breast cancer cells leads to changes in the FOXO3a protein, which then promotes the transcription of the CDK6 gene.
- Targeting the interaction between BRD4 and FOXO3a or inhibiting CDK6 can help overcome resistance to AKT inhibitors, offering new treatment strategies for resistant breast cancer.
Article Abstract
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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Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6281582 | PMC |
| http://dx.doi.org/10.1038/s41467-018-07258-y | DOI Listing |
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