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The Capicua C1 Domain is Required for Full Activity of the CIC::DUX4 Fusion Oncoprotein.

ABSTRACT: Rearrangements between genes can yield neomorphic fusions that drive oncogenesis. Fusion oncogenes are made up of fractional segments of the partner genes that comprise them, with each partner potentially contributing some of its own function to the nascent fusion oncoprotein. Clinically, fusion oncoproteins driving one diagnostic entity are typically clustered into a single molecular subset and are often treated a similar fashion. However, knowledge of where specific fusion breakpoints occur in partner genes, and the resulting retention of functional domains in the fusion, is an important determinant of fusion oncoprotein activity and may differ between patients. This study investigates this phenomena through the example of CIC::DUX4, a fusion between the transcriptional repressor capicua (CIC) and the double homeobox 4 gene (DUX4), which drives an aggressive subset of undifferentiated round cell sarcoma. Using a harmonized dataset of over 100 patient fusion breakpoints from the literature, we show that most bona fide CIC::DUX4 fusions retain the C1 domain, which is known to contribute to DNA binding by wild type CIC. Mechanistically, deletion or mutation of the C1 domain reduces, but does not eliminate, activation of CIC target genes by CIC::DUX4. We also find that expression of C1-deleted CIC::DUX4 is capable of exerting intermediate transformation-related phenotypes compared with those imparted by full-length CIC::DUX4, but was not sufficient for tumorigenesis in a subcutaneous mouse model. In summary, our results suggest a supercharging role for the C1 domain in the activity of CIC::DUX4.

ORGANISM(S): Mus musculus

PROVIDER: GSE279546 | GEO | 2024/10/16

REPOSITORIES: GEO

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The Capicua C1 Domain is Required for Full Activity of the CIC::DUX4 Fusion Oncoprotein

Project description:Rearrangements between genes can yield neomorphic fusions that drive oncogenesis. Fusion oncogenes are made up of fractional segments of the partner genes that comprise them, with each partner potentially contributing some of its own function to the nascent fusion oncoprotein. Clinically, fusion oncoproteins driving one diagnostic entity are typically clustered into a single molecular subset and are often treated a similar fashion. However, knowledge of where specific fusion breakpoints occur in partner genes, and the resulting retention of functional domains in the fusion, is an important determinant of fusion oncoprotein activity and may differ between patients. This study investigates this phenomena through the example of CIC::DUX4, a fusion between the transcriptional repressor capicua (CIC) and the double homeobox 4 gene (DUX4), which drives an aggressive subset of undifferentiated round cell sarcoma. Using a harmonized dataset of over 100 patient fusion breakpoints from the literature, we show that most bona fide CIC::DUX4 fusions retain the C1 domain, which is known to contribute to DNA binding by wild type CIC. Mechanistically, deletion or mutation of the C1 domain reduces, but does not eliminate, activation of CIC target genes by CIC::DUX4. We also find that expression of C1-deleted CIC::DUX4 is capable of exerting intermediate transformation-related phenotypes compared with those imparted by full-length CIC::DUX4, but was not sufficient for tumorigenesis in a subcutaneous mouse model. In summary, our results suggest a supercharging role for the C1 domain in the activity of CIC::DUX4.

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The Capicua C1 Domain is Required for Full Activity of the CIC::DUX4 Fusion Oncoprotein.

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The Capicua C1 Domain is Required for Full Activity of the CIC::DUX4 Fusion Oncoprotein

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The CIC::DUX4 oncoprotein maintains DNA integrity through direct regulation of the catalytic subunit of DNA polymerase epsilon (POLE).

Project description:Transcription factor (TF) fusion oncoproteins represent cancer specific alterations that arise from chromosomal rearrangements. Through target gene recognition, TF fusions can disseminate transcriptional responses that collectively work to drive tumorigenesis. Thus, identifying the molecular targets that operate as a disease driving network can potentially uncover key actionable dependencies. We have taken this strategy to dissect the underlying biological mechanism by which CIC::DUX4, a fusion oncoprotein associated with dismal outcomes, drives sarcomagenesis. We and others have defined a CIC::DUX4 fusion mediated network that dysregulates cell-cycle and DNA replication checkpoints. Specifically, CIC::DUX4-mediated CCNE1 upregulation compromises the G1/S transition leading to high DNA replication stress and conferring a dependence on the G2/M checkpoint kinase, WEE1. Thus, WEE1 provides a molecular brake to enable effective DNA repair prior to mitotic entry. Importantly, the mechanism by which CIC::DUX4 regulates DNA repair remains unknown. Here we show that the catalytic subunit of DNA polymerase epsilon (POLE) is essential for DNA integrity and cellular division in CIC::DUX4 sarcoma. Mechanistically, POLE loss increases DNA damage and induces p21-mediated cellular senescence to limit CIC:DUX4 mediated tumor growth in vitro and tumor formation in vivo. Altogether, we credential POLE as a CIC::DUX4 target and further characterize a functional network through which CIC::DUX4 operates to drive tumor progression and survival.

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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.

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