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CIC-DUX4 chromatin profiling reveals new epigenetic dependencies and actionable therpaeutic targets in CIC-rearranged sarcomas [ChIP-seq]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE248040 | GEO | 2024/01/31

REPOSITORIES: GEO

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CIC-DUX4 chromatin profiling reveals new epigenetic dependencies and actionable therpaeutic targets in CIC-rearranged sarcomas [RNA-seq]

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

Suppression of the CIC-DUX4 oncogene through p300/CBP inhibition

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

Gene expression profiles of mouse CIC-DUX4 sarcoma

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

Expression of the CIC-DUX4 fusion oncoprotein mirrors human CIC-rearranged sarcoma in a transgenic mouse model (ChIP-Seq)

Project description:CIC-DUX4 sarcoma (CDS) is a rare but highly aggressive undifferentiated small round cell sarcoma driven by a fusion between the tumor suppressor Capicua (CIC) and DUX4. Currently, there are no effective treatments and efforts to identify and translate better therapies is limited by the scarcity of tissues and patients. To minimize, we made three genetically engineered mouse models of CDS (Ch7CDS, Ai9CDS, and TOPCDS). Remarkably, chimeric mice from all three models developed spontaneous tumors and widespread metastasis in the absence of Cre-recombinase. The penetrance of spontaneous (Cre-independent) tumor formation was complete irrespective of bi-allelic CIC function and loxP site proximity. Characterization of primary and metastatic mouse tumors showed that they consistently expressed the CIC-DUX4 fusion protein as well as other downstream markers of the disease authenticating them as CDS. Lastly, tumor-derived cell lines were generated and ChIP-seq was preformed to map fusion-gene specific binding using an N-terminal HA epitope tag. These datasets, along with paired H3K27ac ChIP-seq maps, validate CIC-DUX4 as a neomorphic transcriptional activator and point to ETS family transcription factors as cooperative and redundant drivers of the core regulatory circuitry.

2023-10-19 | GSE241370 | GEO

Expression of the CIC-DUX4 fusion oncoprotein mirrors human CIC-rearranged sarcoma in a transgenic mouse model (RNA-Seq)

2023-10-19 | GSE241369 | GEO

Integrated molecular characterization of patient-derived models reveals therapeutic strategies for treating CIC-DUX4 sarcoma.

Project description:Capicua–double homeobox 4 (CIC-DUX4) rearranged sarcomas (CDSs) are extremely rare, highly aggressive primary sarcomas that represent a major therapeutic challenge. To identify selective therapeutic targets of CDS, we performed RNA sequencing of primary tumor samples from patients, patient-derived xenografts (PDXs) and PDX-derived cell lines and we highlighted an HMGA2/IGF2BPs/IGF2/IGF1R/AKT-mTOR axis that characterizes CDS. This highly active axis confers to CDSs sensitivity to both trabectedin, which prevents HMGA proteins from binding to IGF2BP2/3 promoters, and PI3K/mTOR inhibitor NVP-BEZ235 (dactolisib). Combined treatments with trabectedin and NVP-BEZ235 completely abolish the activation of the IGF2/IGF1R/AKT/mTOR axis and the in vivo growth of CDS tumors. The development of representative PDXs and PDX-derived cell lines models has helped to identify the unique sensitivities of CDS towards AKT/mTOR inhibitors and trabectedin, revealing a mechanism-based therapeutic strategy to fight this lethal cancer.

2022-01-12 | GSE165032 | GEO

Expression profiles of Ewing family of tumors authenticate distinct molecular entities

Project description:The concept of Ewing family of tumors (EFT), characterized by FET-ETS fusions, has been recently challenged by the description of Ewing-like tumors with different gene fusions. Here we investigate the similarities and differences of FET-ETS, BCOR-CCNB3, CIC-DUX4 and EWSR1-NFATc2 tumors samples with a number of other sarcomas. Unsupervised clustering of gene expression profiles fully discriminates these four molecular entities. Specific gene signatures and pathways were further validated in model cell lines. While a clear inflammatory signature characterizes EWSR1-NFATc2 tumors, BCOR-CCNB3 and CIC-DUX4 exhibit high expression of homeobox and ETS protein families, respectively. We strongly suggest that abnormalities of chromatin remodeling may gather CIC-DUX4 and BCOR-CCNB3 tumors with rhabdoid tumors and synovial sarcomas. This dataset conains 14 CIC-DUX4 and 7 EWSR1-NFATc2 tumor samples as well as Human mesenchymal cell line expressing EWSR1-NFATc2 (duplicates) or mock treated (duplicates) and IB120 CIC-DUX4 cell line expressing an shRNA directed against CIC-DUX4 (4 replicates) or mock treated (duplicates).

2015-06-30 | E-GEOD-60740 | biostudies-arrayexpress

Suppression of the CIC-DUX4 oncogene through p300/CBP inhibition

Project description:Suppression of the CIC-DUX4 oncogene through p300/CBP inhibition

| PRJNA695547 | ENA

Multi-omic analyses reveal interaction networks linking CIC to cell cycle regulation

Project description:CIC encodes a transcriptional repressor inactivated by loss-of-function mutations in several cancer types, indicating that it may function as a tumor suppressor. Recent data indicate that CIC may regulate cell cycle genes in humans; however, a thorough investigation of this proposed role has not yet been reported. Here, we used single-cell RNA sequencing technology to provide evidence that inactivation of CIC in human cell lines resulted in transcriptional dysregulation of genes involved in cell cycle control. We also mapped CIC’s protein-protein and genetic interaction networks, identifying interactions between CIC and members of the Switch/Sucrose Non-Fermenting (SWI/SNF) complex, as well as novel candidate interactions between CIC and cell cycle regulators. We further showed that CIC loss was associated with an increased frequency of mitotic defects in human cell lines and a mouse model. Overall, our study positions CIC as a cell cycle regulator and indicates that CIC loss can lead to mitotic errors, consistent with CIC’s emerging role as a tumor suppressor of relevance in several cancer contexts.

2023-06-30 | PXD030942 | Pride

DUX4 recruits p300/CBP through its C-terminus and induces global H3K27 acetylation changes

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

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