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| Status |
Public on Feb 21, 2019 |
| Title |
RNA-seq analysis of AKTi MK2206 resistant BT474 and T47D cells |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
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 de-phosphorylation, 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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| Overall design |
Total RNA was extracted from MK2206 resistant cells for RNA sequencing. Parental cells without MK2206 resistance were used as controls.
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| Contributor(s) |
Zhou BP, Shi J |
| Citation(s) |
30518851 |
| |
| Submission date |
Aug 06, 2018 |
| Last update date |
Mar 21, 2019 |
| Contact name |
Binhua P Zhou |
| E-mail(s) |
peter.zhou@uky.edu
|
| Phone |
859-323-4474
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| Organization name |
University of Kentucky School of Medicine
|
| Department |
Markey Cancer Center/Biochemistry
|
| Lab |
Zhou's lab
|
| Street address |
789 South Limestone
|
| City |
Lexington |
| State/province |
KY |
| ZIP/Postal code |
40536 |
| Country |
USA |
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| Platforms (1) |
| GPL20301 |
Illumina HiSeq 4000 (Homo sapiens) |
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| Samples (4)
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| Relations |
| BioProject |
PRJNA484709 |
| SRA |
SRP156436 |
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