Suppression of the CIC-DUX4 oncogene through p300/CBP inhibition
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA695547 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:A recently identified pediatric subtype of undifferentiated round cell sarcoma that is driven by fusion between the cell cycle regulator and transcriptional repressor, capicula (CIC) and the transcriptional activator, DUX4 has been identified based on its histology, clinical differences, and aggressiveness. Because CIC-DUX4 acquires the p300-interacting activation domain of DUX4, we hypothesized that its transcriptional activation potential, and thus the oncogenicity of CIC-DUX4, would require p300 or its homologues, CBP. Recently, a new class of histone acetyltransferase inhibitors with high selectivity for p300 and CBP has been described, and two compounds, A-485, and iP300w, have been shown to inhibit p300 and CBP both in vitro and in vivo with iP300w having the ability to reverse gene expression changes caused by DUX4. If this hypothesis is correct, iP300w should potently counteract the CIC-DUX4 gene expression program and might be a particularly effective therapy for CDS. In this study, we confirm this hypothesis, demonstrating that CIC-DUX4 requires p300/CBP for its activity. We also demonstrate that CIC-DUX4 induces a global increase in H3 acetylation, like DUX4, which is reversible with iP300w treatment. We find that CIC-DUX4 activity is potently blocked by iP300w, and that this compound has potent activity against CDS cell lines and in an in vivo cancer xenograft assay.
2021-10-21 | GSE165729 | GEO
Project description:Ectopic expression of the double homeodomain transcription factor DUX4 causes facioscapulohumeral muscular dystrophy (FSHD). Mechanisms of action of DUX4 are currently unknown. Using immortalized human myoblasts with a titratable DUX4 transgene, we identify by mass spectrometry an interaction between the DUX4 C-terminus and the histone acetyltransferases p300/CBP. Chromatin immunoprecipitation shows that DUX4 recruits p300 to its target gene, ZSCAN4, displaces histone H3 from the center of its binding site, and induces H3K27Ac in its vicinity, but C-terminal deleted DUX4 does not. We show that a DUX4 minigene, bearing only the homeodomains and C-terminus, is transcriptionally functional and cytotoxic, and that overexpression of a nuclear targeted C-terminus impairs the ability of WT DUX4 to interact with p300 and to regulate target genes. Genomic profiling of DUX4, histone H3, and H3 modifications reveals that DUX4 binds two classes of locus: DNase accessible H3K27Ac-rich chromatin and inaccessible H3K27Ac-depleted MaLR-enriched chromatin. At this latter class, it acts as a pioneer factor, recruiting H3K27 acetyltransferase activity and opening the locus for transcription. In concert with local increased H3K27Ac, the strong H3K27Ac peaks at distant sites are significantly depleted of H3K27Ac, thus DUX4 uses its C-terminus to induce a global reorganization of H3K27 acetylation. Two biological samples were analyzed with 4 antibodies for ChIP-Seq and in triplicate for RNA-Seq.
2016-03-10 | E-GEOD-78158 | biostudies-arrayexpress
Project description:CIC-DUX4-rearranged sarcoma (CDS) is a rare and aggressive soft tissue tumor that occurs most frequently in young adults. The key oncogenic driver of this disease is the expression of the CIC-DUX4 fusion protein as a result of chromosomal rearrangements. CIC-DUX4 displays chromatin binding properties, and is therefore believed to function as an aberrant transcription factor. However, the chromatin remodeling events induced by CIC-DUX4 are not well understood, limiting our ability to identify new mechanism-based therapeutic strategies for these patients. Here we generated a genome wide profile of CIC-DUX4 DNA occupancy and associated chromatin states in human CDS cell models and primary tumors. Combining chromatin profiling, proximity ligation assays, as well as genetic and pharmacological perturbations, we show that CIC-DUX4 operates as a potent transcriptional activator at its binding sites. This property is in contrast with the repressive function of the wild type CIC protein, and is mainly mediated through the direct interaction of CIC-DUX4 with the acetyltransferase p300. In keeping with this, we show p300 to be essential for CDS tumor cell proliferation, and its pharmacological inhibition to significantly impact tumor growth in vitro andin vivo. Taken together, our study elucidates the mechanisms underpinning CIC-DUX4-mediated transcriptional regulation and suggests a potential therapeutic approach for the clinical management of CDS patients.
2024-01-31 | GSE248116 | GEO
Project description:CIC-DUX4-rearranged sarcoma (CDS) is a rare and aggressive soft tissue tumor that occurs most frequently in young adults. The key oncogenic driver of this disease is the expression of the CIC-DUX4 fusion protein as a result of chromosomal rearrangements. CIC-DUX4 displays chromatin binding properties, and is therefore believed to function as an aberrant transcription factor. However, the chromatin remodeling events induced by CIC-DUX4 are not well understood, limiting our ability to identify new mechanism-based therapeutic strategies for these patients. Here we generated a genome wide profile of CIC-DUX4 DNA occupancy and associated chromatin states in human CDS cell models and primary tumors. Combining chromatin profiling, proximity ligation assays, as well as genetic and pharmacological perturbations, we show that CIC-DUX4 operates as a potent transcriptional activator at its binding sites. This property is in contrast with the repressive function of the wild type CIC protein, and is mainly mediated through the direct interaction of CIC-DUX4 with the acetyltransferase p300. In keeping with this, we show p300 to be essential for CDS tumor cell proliferation, and its pharmacological inhibition to significantly impact tumor growth in vitro andin vivo. Taken together, our study elucidates the mechanisms underpinning CIC-DUX4-mediated transcriptional regulation and suggests a potential therapeutic approach for the clinical management of CDS patients.
2024-01-31 | GSE248040 | GEO
Project description: Not available
| S-EPMC8511258 | biostudies-literature
Project description:Ectopic expression of the double homeodomain transcription factor DUX4 causes facioscapulohumeral muscular dystrophy (FSHD). Mechanisms of action of DUX4 are currently unknown. Using immortalized human myoblasts with a titratable DUX4 transgene, we identify by mass spectrometry an interaction between the DUX4 C-terminus and the histone acetyltransferases p300/CBP. Chromatin immunoprecipitation shows that DUX4 recruits p300 to its target gene, ZSCAN4, displaces histone H3 from the center of its binding site, and induces H3K27Ac in its vicinity, but C-terminal deleted DUX4 does not. We show that a DUX4 minigene, bearing only the homeodomains and C-terminus, is transcriptionally functional and cytotoxic, and that overexpression of a nuclear targeted C-terminus impairs the ability of WT DUX4 to interact with p300 and to regulate target genes. Genomic profiling of DUX4, histone H3, and H3 modifications reveals that DUX4 binds two classes of locus: DNase accessible H3K27Ac-rich chromatin and inaccessible H3K27Ac-depleted MaLR-enriched chromatin. At this latter class, it acts as a pioneer factor, recruiting H3K27 acetyltransferase activity and opening the locus for transcription. In concert with local increased H3K27Ac, the strong H3K27Ac peaks at distant sites are significantly depleted of H3K27Ac, thus DUX4 uses its C-terminus to induce a global reorganization of H3K27 acetylation.
2016-03-10 | GSE78158 | GEO
Project description:CIC-DUX4 sarcoma (CDS) or CIC-rearranged sarcoma is a subcategory of small round cell sarcoma resembling the morphological phenotypes of Ewing sarcoma (ES). Recent clinicopathologic and molecular genetic analyses indicate that CDS is an independent disease entity from ES. Although a few ancillary markers have been used in the differential diagnosis of CDS, additional CDS-specific biomarkers are needed in challenging diagnosis for a more definitive classification. Here we have generated an ex vivo mouse model for CDS by transducing embryonic mesenchymal cells (eMCs) with human CIC-DUX4 cDNA. The recipient mice transplanted with eMCs expressing CIC-DUX4 rapidly developed an aggressive, undifferentiated sarcoma composed of small round to short spindle cells. Gene expression profiles of CDS and eMCs revealed upregulation of CIC-DUX4 downstream genes such as PEA3 family genes, Ccnd2, Crh and Zic1. Immunohistochemical analyses for both mouse and human tumors showed that CCND2 and MUC5AC are reliable biomarkers to distinguish CDS from ES. Gene silencing of CIC-DUX4 as well as Ccnd2, Ret, and Bcl2, that are upregulated in CDS, effectively inhibited tumor growth in vitro. Palbociclib, a CDK4/6 inhibitor, also showed growth inhibition of mouse CDS cells in vitro, while trabectedin induced tumor suppressive effects both in vitro and in vivo. In summary, the CDS mouse model provides important biological information of CDS and is a useful platform to explore novel biomarkers and therapeutic agents for CDS. We used microarrays to detail the global program of gene expression in mouse CDS.
2017-06-21 | GSE90978 | GEO
Project description:Histone acetylation is important for the activation of gene transcription but little is known about its direct ‘read/write’ mechanisms. Here, we report cryo-electron microscopy structures in which a p300/CBP multidomain monomer recognizes histone H4 N-terminal tail (NT) acetylation (ac) in a nucleosome and acetylates non-H4 histone NTs within the same nucleosome. p300/CBP not only recognized H4NTac via the bromodomain pocket responsible for ‘reading’, but also interacted with the DNA minor grooves via the outside of that pocket. This directed the catalytic center of p300/CBP to one of the non-H4 histone NTs. The primary target that p300 ‘writes’ by ‘reading’ H4NTac was H2BNT, and H2BNTac promoted H2A-H2B dissociation from the nucleosome. We propose a model in which p300/CBP ‘replicates’ histone NT acetylation within the H3-H4 tetramer to inherit epigenetic storage, and ‘transcribes’ it from the H3-H4 tetramer to the H2B-H2A dimers to activate context-dependent gene transcription through local nucleosome destabilization.
2023-05-08 | PXD040835 | Pride