Bharathy, Narendra, Cleary, Megan M, Kim, Jin-Ah, Nagamori, Kiyo, Crawford, Kenneth A, Wang, Eric, Saha, Debarya, Settelmeyer, Teagan P, Purohit, Reshma, Skopelitis, Damianos, Chang, Kenneth, Doran, Jessica A, Kirschbaum, C Ward, Bharathy, Suriya, Crews, Davis W, Randolph, Matthew E, Karnezis, Anthony N, Hudson-Price, Lisa, Dhawan, Jyotsna, Michalek, Joel E, Ciulli, Alessio, Vakoc, Christopher R, Keller, Charles
(January 2022)
SMARCA4 biology in alveolar rhabdomyosarcoma.
Oncogene.
ISSN 0950-9232
Abstract
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and phenocopies a muscle precursor that fails to undergo terminal differentiation. The alveolar subtype (ARMS) has the poorest prognosis and represents the greatest unmet medical need for RMS. Emerging evidence supports the role of epigenetic dysregulation in RMS. Here we show that SMARCA4/BRG1, an ATP-dependent chromatin remodeling enzyme of the SWI/SNF complex, is prominently expressed in primary tumors from ARMS patients and cell cultures. Our validation studies for a CRISPR screen of 400 epigenetic targets identified SMARCA4 as a unique factor for long-term (but not short-term) tumor cell survival in ARMS. A SMARCA4/SMARCA2 protein degrader (ACBI-1) demonstrated similar long-term tumor cell dependence in vitro and in vivo. These results credential SMARCA4 as a tumor cell dependency factor and a therapeutic target in ARMS.
| Item Type: |
Paper
|
| Subjects: |
bioinformatics
diseases & disorders > cancer
diseases & disorders
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics
Investigative techniques and equipment
diseases & disorders > neoplasms
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification
Investigative techniques and equipment > CRISPR-Cas9
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > helicase
diseases & disorders > cancer > prognosis
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types
diseases & disorders > cancer > cancer types > rhabdomyosarcoma
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > transcription factor
diseases & disorders > cancer > cancer types |
| CSHL Authors: |
|
| Communities: |
CSHL labs > Chang lab
CSHL labs > Vakoc lab
CSHL Cancer Center Program
CSHL Cancer Center Program > Cancer Genetics and Genomics Program
CSHL Cancer Center Shared Resources > Functional Genomics and Genetics Service |
| SWORD Depositor: |
CSHL Elements
|
| Depositing User: |
CSHL Elements
|
| Date: |
29 January 2022 |
| Date Deposited: |
03 Feb 2022 16:39 |
| Last Modified: |
09 Feb 2024 17:13 |
| PMCID: |
PMC9985831 |
| URI: |
https://repository.cshl.edu/id/eprint/40507 |
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