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| Status |
Public on Sep 15, 2016 |
| Title |
Loss of HDAC-mediated repression and gain of NF-kB activation underlies cytokine induction in ARID1A and PIK3CA mutation-driven ovarian cancer |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
|
| Summary |
ARID1A is frequently mutated in ovarian clear-cell carcinoma (OCCC) and often co-exists with activating mutations of PIK3CA. Although induction of pro-inflammatory cytokines has been observed in this cancer, the mechanism by which the two mutations synergistically activate cytokine genes remains elusive. Here we established an in vitro model of OCCC by introducing ARID1A knock-down and mutant PIK3CA in a normal human ovarian epithelial cell line, which resulted in cell transformation and cytokine gene induction. We demonstrate that loss of ARID1A impairs the recruitment of the Sin3A-HDAC complex, while PIK3CA mutation releases RelA from IkB, leading to cytokine gene activation. We show that an NF-kB inhibitor partly attenuates proliferation of OCCC and improves the efficacy of carboplatin both in cell culture and a mouse model. Our study thus reveals the mechanistic link between ARID1A/PIK3CA mutations and cytokine gene induction in OCCC, and suggests NF-kB inhibition can be a potential therapeutic option.
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| |
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| Overall design |
Examine transcriptome and chromatin accessibility differences between human WT ovarian cells and cells with single or double mutations.
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| |
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| Contributor(s) |
Kim M, Lu F, Zhang Y |
| Citation(s) |
27681437 |
| |
| Submission date |
Aug 24, 2016 |
| Last update date |
Dec 22, 2020 |
| Contact name |
Falong Lu |
| E-mail(s) |
falonglu@gmail.com
|
| Organization name |
Boston Children's Hospital / HHMI
|
| Department |
Program of Cellular and Molecular Medicine
|
| Lab |
Yi Zhang
|
| Street address |
200 Longwood Ave, WAB 159
|
| City |
Boston |
| State/province |
Massachusetts |
| ZIP/Postal code |
02115 |
| Country |
USA |
| |
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| Platforms (1) |
| GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
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| Samples (12)
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| Relations |
| BioProject |
PRJNA339979 |
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