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| Status |
Public on Jan 03, 2019 |
| Title |
SMARCA4 loss is synthetic lethal with CDK4/6 via restriction CCND1 chromatin accessibility in lung cancer |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
Tumor suppressor SMARCA4 (BRG1), a key SWI/SNF chromatin remodelling gene, is frequently inactivated in cancers which is not directly druggable. We recently uncovered that SMARCA4 loss in an ovarian cancer subtype causes cyclin D1 deficiency leading to susceptibility to CDK4/6 inhibition. Here, we show that this vulnerability is conserved in non-small cell lung cancer (NSCLC), where SMARCA4 loss also results in reduced cyclin D1 expression and selective sensitivity to CDK4/6 inhibitors. In addition, SMARCA2, another SWI/SNF subunit lost in a subset of NSCLCs, also regulates cyclin D1 and drug response when SMARCA4 is absent. Mechanistically, SMARCA2/4 loss reduces cyclin D1 expression by a combination of restricting CCND1 chromatin accessibility and suppressing c-jun, a transcription activator of CCND1. Furthermore, SMARCA4 loss is synthetic lethal with CDK4/6 inhibition both in vitro and in vivo, suggesting that FDA-approved CDK4/6 inhibitors could be effective to treat this significant subgroup of NSCLCs.
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| Overall design |
This dataset includes 3-ATAC-seq and 11 ChIP-seq samples
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| Contributor(s) |
Huang S, Pastor WA |
| Citation(s) |
30718506 |
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| Submission date |
Oct 24, 2018 |
| Last update date |
Mar 27, 2019 |
| Contact name |
William Abraham Pastor |
| E-mail(s) |
william.pastor@mcgill.ca
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| Phone |
514-618-3348
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| Organization name |
McGill University
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| Department |
Biochemistry
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| Lab |
Pastor
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| Street address |
3655 Promenade Sir William Osler
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| City |
Montreal |
| State/province |
QC |
| ZIP/Postal code |
H3G 1Y6 |
| Country |
USA |
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| Platforms (1) |
| GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
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| Samples (14)
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| Relations |
| BioProject |
PRJNA498319 |
| SRA |
SRP166789 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE121755_RAW.tar |
1.2 Gb |
(http)(custom) |
TAR (of BW) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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