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| Status |
Public on Mar 22, 2024 |
| Title |
Targeting DCAF5 suppresses SMARCB1-mutant cancer via stabilizing SWI/SNF |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
Third-party reanalysis
|
| Summary |
While oncogenes can potentially be inhibited with small molecules, the loss of tumor suppressors is more common and presents a conundrum for precision therapy because the proteins are no longer present. SMARCB1-mutant cancers epitomize this challenge because these highly lethal cancers are driven by inactivation of a single gene, a subunit of SWI/SNF chromatin remodeling complexes. To generate mechanistic insight into the consequences of SMARCB1 mutation and to seek vulnerabilities, we contributed 16 SMARCB1-mutant cell lines to a near-genomewide CRISPR screen as part of the Cancer Dependency Map1-3. Here we report that the little-studied gene DCAF5 (DDB1-CUL4 Associated Factor 5) is a specific dependency in SMARCB1-mutant cancers. We show that DCAF5 serves a quality control function for SWI/SNF complexes and in the absence of SMARCB1 DCAF5 causes degradation of incompletely assembled SWI/SNF complexes. Upon inhibition of DCAF5 SMARCB1-deficient SWI/SNF complexes re-accumulate, bind to target loci, and restore gene expression to levels sufficient to fully reverse the cancer state, including in a xenograft mouse model. Consequently, cancer results not from the loss of SMARCB1 function per se but rather from DCAF5-mediated degradation of SWI/SNF complexes. These data indicate that therapeutic targeting of DCAF5 may be sufficient to restore substantial SWI/SNF function and reverse cancer phenotypes caused by SMARCB1 loss.
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| Overall design |
ATAC-seq in G401 cells: shCTRL(n=3), shDCAF5(n=3)
ATAC-Seq performed in triplicate in G401 cells treated with the combination of shDCAF5 with ATPase inhibitor BRM014 (1uM) with proper controls. Reprocessed ATAC-Seq data in triplicate for G401s with and without SMARCB1 added back
Re-analysed Samples GSE210632/PRJNA866528 and processed data files:
GSM6433872 SRX16881727 SAMN30167975 2112966_GFP_ATAC_n1.free*
GSM6433873 SRX16881728 SAMN30167974 2118889_GFP_ATAC_n2.free*
GSM6433874 SRX16881729 SAMN30167973 2161067_GFP_ATAC_n3.free*
GSM6433875 SRX16881730 SAMN30167972 2112968_SMARCB1_ATAC_n1.free*
GSM6433876 SRX16881719 SAMN30167971 2118891_SMARCB1_ATAC_n2.free*
GSM6433877 SRX16881720 SAMN30167970 2161068_SMARCB1_ATAC_n3.free*
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| Contributor(s) |
Myers JA, Roberts CW, Radko-Juettner S |
| Citation(s) |
38538798 |
| |
| Submission date |
Oct 07, 2022 |
| Last update date |
Apr 12, 2024 |
| Contact name |
Jacquelyn A Myers |
| E-mail(s) |
jamyers2358@gmail.com
|
| Organization name |
St. Jude Children’s Research Hospital
|
| Street address |
262 Danny Thomas Pl
|
| City |
Memphis |
| State/province |
TN |
| ZIP/Postal code |
38105 |
| Country |
USA |
| |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
|
| Samples (24)
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| This SubSeries is part of SuperSeries: |
| GSE215025 |
Targeting DCAF5 suppresses SMARCB1-mutant cancer via stabilizing SWI/SNF |
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| Relations |
| BioProject |
PRJNA888094 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE215022_2112966_GFP_ATAC_n1.free.bw |
142.0 Mb |
(ftp)(http) |
BW |
| GSE215022_2112966_GFP_ATAC_n1.free_macs2.filter.narrowPeak.gz |
2.6 Mb |
(ftp)(http) |
NARROWPEAK |
| GSE215022_2112968_SMARCB1_ATAC_n1.free.bw |
140.1 Mb |
(ftp)(http) |
BW |
| GSE215022_2112968_SMARCB1_ATAC_n1.free_macs2.filter.narrowPeak.gz |
4.2 Mb |
(ftp)(http) |
NARROWPEAK |
| GSE215022_2118889_GFP_ATAC_n2.free.bw |
69.1 Mb |
(ftp)(http) |
BW |
| GSE215022_2118889_GFP_ATAC_n2.free_macs2.filter.narrowPeak.gz |
1.9 Mb |
(ftp)(http) |
NARROWPEAK |
| GSE215022_2118891_SMARCB1_ATAC_n2.free.bw |
160.6 Mb |
(ftp)(http) |
BW |
| GSE215022_2118891_SMARCB1_ATAC_n2.free_macs2.filter.narrowPeak.gz |
4.6 Mb |
(ftp)(http) |
NARROWPEAK |
| GSE215022_2161067_GFP_ATAC_n3.free.bw |
88.2 Mb |
(ftp)(http) |
BW |
| GSE215022_2161067_GFP_ATAC_n3.free_macs2.filter.narrowPeak.gz |
2.1 Mb |
(ftp)(http) |
NARROWPEAK |
| GSE215022_2161068_SMARCB1_ATAC_n3.free.bw |
221.3 Mb |
(ftp)(http) |
BW |
| GSE215022_2161068_SMARCB1_ATAC_n3.free_macs2.filter.narrowPeak.gz |
4.5 Mb |
(ftp)(http) |
NARROWPEAK |
| GSE215022_RAW.tar |
5.8 Gb |
(http)(custom) |
TAR (of BW, NARROWPEAK) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
| Processed data are available on Series record |
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