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| Status |
Public on Sep 09, 2020 |
| Title |
An epigenetic vulnerability in PI3K/AKT inhibition resistant cancers is targetable by both bromodomain and HDAC inhibitors |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
Acquisition of resistance to PI3K/AKT-targeted monotherapy regardless of cancer types implies the existence of common mechanisms. Here we demonstrate that while causing glycolysis crisis, acetyl-CoA shortage and global decrease of histone acetylation, PI3K/AKT inhibitors induce drug resistance by selectively augmenting CBP/p300, H3K27 acetylation and BRD4 binding at genomic loci of a subset of growth factor and receptor (GF/R) genes. BRD4 occupation at these loci and drug resistant cell growth are vulnerable to both bromodomain and HDAC inhibitors. Little or none occupation of HDACs at the GF/R gene loci underscores the paradox that cells respond equivalently to the two classes of inhibitors with opposite modes of action. Targeting this unique epigenetic vulnerability offers a general solution to overcome PI3K/AKT inhibitor resistance in different cancers.
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| Overall design |
ChIP-seqs were performed in the PC-3 control and GDC-R cells treated with iCBP112 or SAHA, using antibody of H3K27-ac, H3K9/K14-ac, H4-ac,CBP/p300, HDAC1/2 and BRD4 (Drosophila S2 cell chromatin was used as spike-in control for H3K27-ac ChIP-seq).
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| Contributor(s) |
Huang H, Wu D, Wang L, Ye Z, Wei T |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
| |
| Submission date |
Mar 24, 2020 |
| Last update date |
Sep 13, 2020 |
| Contact name |
Zhenqing Ye |
| E-mail(s) |
iamyezhenqing@gmail.com
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| Organization name |
UT Health San Antonio
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| Department |
6Department of Population Health Sciences
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| Street address |
8403 Floyd Curl Dr
|
| City |
San Antonio |
| State/province |
TX |
| ZIP/Postal code |
78229 |
| Country |
USA |
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| Platforms (1) |
| GPL20301 |
Illumina HiSeq 4000 (Homo sapiens) |
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| Samples (32)
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| GSM4431246 |
PC3 control+vehicle H3K27-ac (S2 cell Spike-in) rep1 |
| GSM4431247 |
PC3 control+vehicle H3K27-ac (S2 cell Spike-in) rep2 |
| GSM4431248 |
PC3 GDC-resist+vehicle H3K27-ac (S2 cell Spike-in) rep1 |
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| This SubSeries is part of SuperSeries: |
| GSE137209 |
Bromodomain and HDAC inhibitors equivalently suppress PI3K/AKT inhibition resistance in cancers |
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| Relations |
| BioProject |
PRJNA614914 |
| SRA |
SRP253852 |
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