CRISPR screen identifies the NCOR/HDAC3 complex as a major suppressor of differentiation in rhabdomyosarcoma
Open accessAbstract
Dysregulated gene expression resulting from abnormal epigenetic alterations including histone acetylation and deacetylation has been demonstrated to play an important role in driving tumor growth and progression. However, the mechanisms by which specific histone deacetylases (HDACs) regulate differentiation in solid tumors remains unclear. Using pediatric rhabdomyosarcoma (RMS) as a paradigm to elucidate the mechanism blocking differentiation in solid tumors, we identified HDAC3 as a major suppressor of myogenic differentiation from a high-efficiency Clustered regularly interspaced short palindromic repeats (CRISPR)-based phenotypic screen of class I and II HDAC genes. Detailed characterization of the HDAC3-knockout phenotype in vitro and in vivo using a tamoxifen-inducible CRISPR targeting strategy demonstrated that HDAC3 deacetylase activity and the formation of a functional complex with nuclear receptor corepressors (NCORs) were critical in restricting differentiation in RMS. The NCOR/HDAC3 complex specifically functions by blocking myoblast determination protein 1 (MYOD1)-mediated activation of myogenic differentiation. Interestingly, there was also a transient up-regulation of growth-promoting genes upon initial HDAC3 targeting, revealing a unique cancer-specific response to the forced transition from a neoplastic state to terminal differentiation. Our study applied modifications of CRISPR/CRISPR-associated endonuclease 9 (Cas9) technology to interrogate the function of essential cancer genes and pathways and has provided insights into cancer cell adaptation in response to altered differentiation status. Because current pan-HDAC inhibitors have shown disappointing results in clinical trials of solid tumors, therapeutic targets specific to HDAC3 function represent a promising option for differentiation therapy in malignant tumors with dysregulated HDAC3 activity.
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In pediatric rhabdomyosarcomas, the HDAC3/NCOR1/NCOR2 complex acts as a differentiation brake.
“In pediatric rhabdomyosarcomas the HDAC3/NCOR1/NCOR2 complex acts as a differentiation brake.”
From HDACs and the epigenetic plasticity of cancer cells: target the complexity (2022) · cites this paper as Phelps et al., 2016
Its deletion reactivates the MYOD1-dependent myogenic program.
“Its deletion reactivates the MYOD1-dependent myogenic program.”
From HDACs and the epigenetic plasticity of cancer cells: target the complexity (2022) · cites this paper as Phelps et al., 2016
Downregulation of HDAC4 also promoted the myogenic program, albeit to a lesser extent.
“Interestingly, the downregulation of HDAC4, albeit to a lesser extent, also promoted the myogenic program (Phelps, Bailey, Vleeshouwer-Neumann, & Chen, 2016).”
From HDACs and the epigenetic plasticity of cancer cells: target the complexity (2022) · cites this paper as Phelps et al., 2016
HDAC3 was identified by a CRISPR/Cas9-based phenotypic screen of class I and class II HDAC genes.
“HDAC3 was identified by a CRISPR/Cas9-based phenotypic screen of class I and class II HDAC genes.”
From HDACs and the epigenetic plasticity of cancer cells: target the complexity (2022) · cites this paper as Phelps et al., 2016
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HDACs and the epigenetic plasticity of cancer cells: target the complexity
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- Authors
- Phelps, M. P., Bailey, J. N., Vleeshouwer-Neumann, T., & Chen, E. Y.
- Affiliations
- University of Washington (US)
- Corresponding author
- Chen, Eleanor Y.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2016-12-12
- Volume
- 113
- Issue
- 52
- Pages
- 15090-15095
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC5206534
- OpenAlex
- W2561117921
- Cited by
- 62
- References
- 23
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 4 · 2023: 7 · 2022: 9 · 2021: 10 · 2020: 9 · 2019: 5 · 2018: 4 · 2017: 2
- FWCI
- 1.57
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- HHS | NIH | National Cancer Institute (R01CA196882)
- HHS | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases (K08AR063165)
- St. Baldrick's Foundation (N/A)
- Rally Foundation (N/A)
- Sarcoma Foundation of America (N/A)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Sarcoma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- rhabdomyosarcoma, HDAC3, NCoR, nuclear receptor corepressor, histone deacetylase, myogenesis, MyoD, epigenetic regulation, CRISPR screen, differentiation therapy, histone acetylation, tumor suppressor, HDAC3 inhibitors
- MeSH terms
- Histone Deacetylase 3, Animals, Cell Differentiation, Histone Deacetylases, Humans, Neoplasm Transplantation, Phenotype, Protein Processing, Post-Translational, Rhabdomyosarcoma, Genome, Human, Gene Expression Regulation, Neoplastic, Gene Deletion, Muscle Neoplasms, Gene Expression Profiling, Mice, Histone Deacetylase Inhibitors, Co-Repressor Proteins, Nuclear Receptor Co-Repressor 1, Clustered Regularly Interspaced Short Palindromic Repeats
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