Inactivation of the CIC-DUX4 oncogene through P300/CBP inhibition, a therapeutic approach for CIC-DUX4 sarcoma

Bosnakovski, Darko; Ener, Elizabeth T.; Cooper, Mark; Gearhart, Micah D.; Knights, Kevin A.; Xu, Natalie; Palumbo, Christian A; Toso, Erik A.; Marsh, Graham P.; Maple, Hannah J.; Kyba, Michael

doi:10.1038/s41389-021-00357-4

Cited by 25 publications

(26 citation statements)

References 51 publications

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“…The DUX4 C‐terminus recruits p300/CBP, inducing a drastic increase of histone H3K27 acetylation, and p300 inhibition induces cell death via global histone H3 hyperacetylation 109,110 . The finding was supported by the result that the treatment with the p300/CBP inhibitor iP300w inhibited the proliferation of CIC::DUX4 sarcoma cells 111 . CIC::DUX4 upregulates genes of oncogenic pathways such as ETV1/4/5 and Cyclin D/E 112,113 .…”

Section: Epigenetic Aberrations In Bone and Soft Tissue Sarcomas And ...mentioning

confidence: 92%

Targeting epigenetic aberrations of sarcoma in CRISPR era

Tanaka

Nakamura

2023

Genes Chromosomes & Cancer

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Sarcomas are rare malignancies that exhibit diverse biological, genetic, morphological, and clinical characteristics. Genetic alterations, such as gene fusions, mutations in transcriptional machinery components, histones, and DNA methylation regulatory molecules, play an essential role in sarcomagenesis. These mutations induce and/or cooperate with specific epigenetic aberrations required for the growth and maintenance of sarcomas. Appropriate mouse models have been developed to clarify the significance of genetic and epigenetic interactions in sarcomas. Studies using the mouse models for human sarcomas have demonstrated major advances in our understanding the developmental processes as well as tumor microenvironment of sarcomas. Recent technological progresses in epigenome editing will not only improve the studies using animal models but also provide a direct clue for epigenetic therapies. In this manuscript, we review important epigenetic aberrations in sarcomas and their representative mouse models, current methods of epigenetic editing using CRISPR/ dCas9 systems, and potential applications in sarcoma studies and therapeutics.

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Section: Epigenetic Aberrations In Bone and Soft Tissue Sarcomas And ...mentioning

confidence: 92%

Targeting epigenetic aberrations of sarcoma in CRISPR era

Tanaka

Nakamura

2023

Genes Chromosomes & Cancer

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“…1k). The DUX4 activation domain is exquisitely dependent on the histone acetyltransferase (HAT) activity of p300 and CBP 27,28 . We found that H3 acetylation driven by sDUX was reversed by treatment with iP300w (Fig.…”

Section: Sdux Binds Dux Motifs and Is Toxic To Human Myoblastsmentioning

confidence: 99%

Antagonism among DUX family members evolved from an ancestral toxic single homeodomain protein

Bosnakovski

Toso

Ener

et al. 2023

Preprint

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Double homeobox (DUX) genes are unique to eutherian mammals and normally expressed transiently during zygotic genome activation. The canonical member, DUX4, is involved in facioscapulohumeral muscular dystrophy (FSHD) and cancer, when misexpressed in other contexts. We evaluate the 3 human DUX genes and the ancestral single homeobox gene sDUX from the non-eutherian mammal, platypus, and find that DUX4 activities are not shared with DUXA or DUXB, which lack transcriptional activation potential, but surprisingly are shared with platypus sDUX. In human myoblasts, platypus sDUX drives cytotoxicity, inhibits myogenesis, and induces DUX4 target genes, particularly those associated with zygotic genome activation (ZGA), by binding DNA as a homodimer in a way that overlaps the DUX4 homeodomain crystal structure. DUXA lacks transcriptional activity but has DNA-binding and chromatin accessibility overlap with DUX4 and sDUX, including on ZGA genes and LTR elements, and can actually be converted into a DUX4-like cytotoxic factor by fusion to a synthetic transactivation domain. DUXA competition antagonizes the activity of DUX4 on its target genes, including in FSHD patient cells. Since DUXA is an early DUX4 target gene, this activity potentiates feedback inhibition, constraining the window of DUX4 activity. The DUX gene family therefore comprises cross-regulating members of opposing function, with implications for their roles in ZGA, FSHD, and cancer.

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“…NCC-CDS2-C1 cells harbored a CIC::DUX4 fusion without insertion and exhibited rapid growth, spheroid formation, and invasion. Bosnakovski et al [28 ▪ ] have demonstrated that the CIC::DUX4 chimeric protein requires P300/CBP to induce histone H3 acetylation, activate its targets, and drive oncogenesis. They have described the synthetic route to a selective and highly potent P300/CBP inhibitor named iP300w and related stereoisomers, and found that iP300w efficiently suppress CIC::DUX4 transcriptional activity and reverses CIC::DUX4 induced histone H3 acetylation.…”

Section: Therapeutic Options For Cic-dux4 Sarcomamentioning

confidence: 99%

CIC-DUX4 sarcomas

Brahmi

Vanacker

Macagno

et al. 2022

Current Opinion in Oncology

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Purpose of reviewCIC-DUX4 sarcoma (CDS) is a high-grade undifferentiated round cells sarcoma that belongs to the undifferentiated round cell sarcomas family. It represents less than one percent of sarcomas, defining a rarest among rare malignancies. It affects young adults, displaying soft tissue mass. Considered very aggressive, a high proportion of cases display an advanced disease with lung metastasis at diagnosis. Here we discuss recent progress in molecular characterization of CDS, the main tracks of CDS biology and the current and future prospects of therapeutic approaches.Recent findingsCDS is characterized by a specific oncogenic translocation CIC::DUX4 that induce ETV4 overexpression. Patients with CDS show an aggressive clinical course and have a significantly unfavorable outcome compared to Ewing sarcoma. As of today, there is a lack of consensus on whether they should be treated with an Ewing-like approach, as currently done by most sites, or regarded as high-grade soft tissue sarcoma (STS). Anyway, when feasible, combination regimens including anthracycline and alkylating agents should be favored and patients should not benefit from a therapeutic de-escalation. Overall, registration within clinical trials and prospective registries is recommended.SummaryOverall, CDS showed a poor prognosis regardless of the patterns of treatment that warrant biological studies to better understand the disease.

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Inactivation of the CIC-DUX4 oncogene through P300/CBP inhibition, a therapeutic approach for CIC-DUX4 sarcoma

Cited by 25 publications

References 51 publications

Targeting epigenetic aberrations of sarcoma in CRISPR era

Targeting epigenetic aberrations of sarcoma in CRISPR era

Antagonism among DUX family members evolved from an ancestral toxic single homeodomain protein

CIC-DUX4 sarcomas

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