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| Status |
Public on Oct 30, 2019 |
| Title |
ARID1A and the BAF complex are determinants of breast cancer treatment response [CRISPR gRNA-seq] |
| Organism |
Homo sapiens |
| Experiment type |
Other
|
| Summary |
Global CRISPR screens provide an unparalleled, longer-term experimental approach for the identification of essential genes in drug resistance. We used an ~18,000 gene deletion screen to discover ARID1A and other BAF complex components as the most critical factors required for response to two classes of Estrogen Receptor (ER) antagonists, namely ER degraders and Selective Estrogen Receptor Modulators (SERMs). Unexpectedly, ARID1A was also the top candidate for response to the BET inhibitor JQ1, but in the opposite direction, where loss of ARID1A sensitised breast cancer cells to BET inhibition. We show that ARIDA binds chromatin at ER cis-regulatory elements and can physically associate with ER in model systems and primary tumour samples. ARID1A binding to ER enhancer elements, can occur in the absence of ER, suggesting that its repressive activity occurs in an enhancer-specific, but ER-independent manner. Specific targeting of ARID1A validated the CRISPR screen and shows that depletion of BAF activity, does not result in redundancy from P-BAF, the other ATP-dependent chromatin remodelling complex, but instead results in loss of HDAC1 binding, increased Histone 4 lysine acetylation and subsequent BRD4-driven growth. ARID1A and the BAF complex therefore function as a critical mechanism of antiestrogen activity and mutation or depletion in BAF activity drives a BRD4-mediated proliferative program that is refractory to ER targeted agents. Since ARID1A is mutated in a subset of treatment-resistant disease, these findings provide mechanistic insight and treatment strategies for patients, based on BAF complex fidelity status.
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| Overall design |
CRISPR gRNA sequencing of Cas9 expressing MCF7 cells infected with pooled gRNA libraries with different days of infection and with drug treatments (JQ1, 4-hydroxytamoxifen and Fulvestrant).
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| Contributor(s) |
Nagarajan S, Chernukhin I, Carroll JS |
| Citation(s) |
31913353 |
| |
| Submission date |
Dec 03, 2018 |
| Last update date |
Feb 07, 2020 |
| Contact name |
Jason Carroll |
| E-mail(s) |
Jason.Carroll@cruk.cam.ac.uk
|
| Phone |
+44 1223 769649
|
| Organization name |
Cancer Research UK, Cambridge Institute
|
| Street address |
Li Ka Shing Centre, Robinson Way
|
| City |
Cambridge |
| ZIP/Postal code |
CB2 ORE |
| Country |
United Kingdom |
| |
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| Platforms (1) |
| GPL20301 |
Illumina HiSeq 4000 (Homo sapiens) |
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| Samples (35)
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| This SubSeries is part of SuperSeries: |
| GSE123286 |
ARID1A and the BAF complex are determinants of breast cancer treatment response |
|
| Relations |
| BioProject |
PRJNA508099 |
| SRA |
SRP172093 |
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