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| Status |
Public on Dec 20, 2019 |
| Title |
Three-dimensional Oxabicycloheptene sulfonate targets the homologous recombination and repair programs through estrogen receptor α antagonism |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
Expression profiling by high throughput sequencing
|
| Summary |
Selective Estrogen Receptor Modulators (SERMs) are a class of structurally diverse compounds possessing unique partially agonistic and antagonistic properties and have been extensively used in treatments of hormone-responsive cancers and other diseases. Our previous studies have identified a three-dimensional SERM oxabicycloheptene sulfonate (OBHS) for estrogen receptor α (ERα), which is effective in vivo for the prevention and treatment of estrogen-dependent endometriosis. Here, using ChIP-seq and RNA-seq analysis, we found that OBHS rapidly induces genome-wide ERα occupancy behaves as a partial agonist and antagonist in ERα positive MCF-7 cells. Interestingly, OBHS downregulates the homologous recombination and repair (HRR) modules resulting in the increased DNA damage, apoptosis and cell cycle arrest, and leading to synthetic lethality with Poly (ADP-ribose) polymerase (PARP) inhibitor olaparib and genotoxic doxorubicin through blocking of ERα. Furthermore, we found that OBHS treatment results in defects of RNA polymerase II loading at the estrogen-responsive HRR genes, providing a mechanism for the regulation of HRR genes by OBHS. Together, our studies not only reveal a novel SERM OBHS which uniquely targets the homologous recombination and repair programs through ERα antagonism, but also propose a synthetic lethal strategy by combining OBHS with PARP inhibitor olaparib or genotoxic doxorubicin for ERα-responsive cancers.
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| Overall design |
Determination of the gene exression profiles by estrogen or OBHS for 12 hours, examination of the genome-wide ERα and Pol II occupancy after treatment of estrogen or OBHS for 1 hour.
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| Web link |
https://www.ncbi.nlm.nih.gov/pubmed/31629931
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| |
|
| Contributor(s) |
Liang K, Huang J |
| Citation(s) |
31629931 |
| |
| Submission date |
Jul 08, 2019 |
| Last update date |
Dec 23, 2019 |
| Contact name |
Kaiwei Liang |
| E-mail(s) |
kwliang@whu.edu.cn
|
| Phone |
+86-13476203020
|
| Organization name |
Wuhan University
|
| Street address |
# 185 Dong Hu Road
|
| City |
Wuhan |
| State/province |
Hubei |
| ZIP/Postal code |
430071 |
| Country |
China |
| |
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| Platforms (2) |
| GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
|
| Samples (13)
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| Relations |
| BioProject |
PRJNA553179 |
| SRA |
SRP213630 |
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