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| Status |
Public on Dec 31, 2019 |
| Title |
Combination Targeting of the Bromodomain and Acetyltransferase Active Site of p300/CBP [RNA-seq] |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
p300 and CBP are highly related histone acetyltransferase (HAT) enzymes that regulate gene expression, and their dysregulation has been linked to cancer and other diseases. p300/CBP is composed of a number of domains including a HAT domain which is inhibited by the small molecule A-485 and an acetyl-lysine binding bromodomain which was recently found to be selectively antagonized by the small molecule I-CBP112. Here we show that the combination of I-CBP112 and A-485 can synergize to inhibit prostate cancer cell proliferation. We find that the combination confers a dramatic reduction in p300 chromatin occupancy compared to the individual effects of blocking either domain alone. Accompanying this loss of p300 on chromatin, combination treatment predominantly leads to the reduction of specific mRNAs including androgen-dependent and pro-oncogenic prostate genes such as KLK3 (PSA) and c-Myc. Consistent with p300 chromatin binding directly affecting gene expression, mRNAs that are significantly reduced by combination treatment also exhibit a strong reduction in p300 chromatin occupancy at their gene promoters. The relatively few mRNAs that are up-regulated upon combination treatment show no correlation with p300 occupancy. These studies provide support for the pharmacologic advantage of concurrent targeting of two domains within one key epigenetic modification enzyme.
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| Overall design |
LNCaP cells were divided into 4 different drug treatment groups (including DMSO control) and were treated with I-CBP112 and/or A-485 for 24 h after which they were analyzed for total mRNA levels.
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| Contributor(s) |
Zucconi BE, Cole PA |
| Citation(s) |
30924641 |
| |
| Submission date |
Jan 03, 2019 |
| Last update date |
Jan 14, 2020 |
| Contact name |
Beth Zucconi |
| E-mail(s) |
bethzucconi@gmail.com
|
| Organization name |
Brigham & Women's Hospital
|
| Department |
Medicine
|
| Lab |
P.A. Cole
|
| Street address |
77 Avenue Louis Pasteur, NRB 164
|
| City |
Boston |
| State/province |
Massachusetts |
| ZIP/Postal code |
02115 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
|
| Samples (8)
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| This SubSeries is part of SuperSeries: |
| GSE124644 |
Combination Targeting of the Bromodomain and Acetyltransferase Active Site of p300/CBP |
|
| Relations |
| BioProject |
PRJNA512902 |
| SRA |
SRP175116 |
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