Inactivation of the CIC-DUX4 Oncogene Through P300/CBP Inhibition, a Therapeutic Approach for CIC-DUX4 Sarcoma

Overview

Journal Oncogenesis

Date 2021 Oct 13

PMID 34642317

Citations 20

Authors

Darko Bosnakovski

Elizabeth T Ener

Mark S Cooper

Micah D Gearhart

Kevin A Knights

Natalie C Xu

Christian A Palumbo

Erik A Toso

Graham P Marsh

Hannah J Maple

Michael Kyba

Affiliations

Soon will be listed here.

Abstract

CIC-DUX4 sarcoma (CDS) is a highly aggressive and metastatic small round type of predominantly pediatric sarcoma driven by a fusion oncoprotein comprising the transcriptional repressor Capicua (CIC) fused to the C-terminal transcriptional activation domain of DUX4. CDS rapidly develops resistance to chemotherapy, thus novel specific therapies are greatly needed. We demonstrate that CIC-DUX4 requires P300/CBP to induce histone H3 acetylation, activate its targets, and drive oncogenesis. We describe the synthetic route to a selective and highly potent P300/CBP inhibitor named iP300w and related stereoisomers, and find that iP300w efficiently suppresses CIC-DUX4 transcriptional activity and reverses CIC-DUX4 induced acetylation. iP300w is active at 100-fold lower concentrations than related stereoisomers or A-485. At low doses, iP300w shows specificity to CDS cancer cell lines, rapidly inducing cell cycle arrest and preventing growth of established CDS xenograft tumors when delivered in vivo. The effectiveness of iP300w to inactivate CIC-DUX4 highlights a promising therapeutic opportunity for CDS.

Citing Articles

The important role of the histone acetyltransferases p300/CBP in cancer and the promising anticancer effects of p300/CBP inhibitors.

Wu X, Zhang X, Tang S, Wang Y Cell Biol Toxicol. 2025; 41(1):32.

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

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Wei E, Mitanoska A, OBrien Q, Porter K, Molina M, Ahsan H Mol Cancer. 2024; 23(1):222.

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Epigenetic determinants of fusion-driven sarcomas: paradigms and challenges.

Stanton B, Pomella S Front Cell Dev Biol. 2024; 12:1416946.

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