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Associated Chromosome Trap for Identifying Long-range DNA Interactions
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CIC-DUX4 Chromatin Profiling Reveals New Epigenetic Dependencies and Actionable Therapeutic Targets in CIC-Rearranged

Arnaud Bakaric1, Luisa Cironi2, Viviane Praz3

  • 1Clinical Pathology Service, Department of Diagnostics, Geneva University Hospital, 1205 Geneva, Switzerland.

Cancers
|January 26, 2024
PubMed

Insights

CIC-DUX4-rearranged sarcoma (CDS) is driven by a fusion protein that acts as a transcriptional activator. Targeting the p300 protein, essential for CDS cell growth, offers a promising therapeutic strategy for this rare cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • CIC-DUX4-rearranged sarcoma (CDS) is a rare, aggressive soft tissue tumor primarily affecting young adults.
  • The CIC-DUX4 fusion protein, resulting from chromosomal rearrangements, is the main oncogenic driver in CDS.
  • Understanding CIC-DUX4's chromatin remodeling role is crucial for developing targeted therapies.

Purpose of the Study:

  • To elucidate the genome-wide DNA occupancy and chromatin states associated with CIC-DUX4.
  • To investigate the mechanism of CIC-DUX4's transcriptional regulation.
  • To explore therapeutic strategies targeting CIC-DUX4's function.

Main Methods:

  • Genome-wide profiling of CIC-DUX4 DNA occupancy and chromatin states in CDS models and tumors.
  • Chromatin profiling, proximity ligation assays, genetic, and pharmacological perturbations.
  • In vitro and in vivo studies assessing the impact of p300 inhibition.

Main Results:

  • CIC-DUX4 functions as a potent transcriptional activator, unlike wild-type CIC.
  • CIC-DUX4 directly interacts with the acetyltransferase p300 to mediate its function.
  • p300 is essential for CDS tumor cell proliferation, and its inhibition significantly reduces tumor growth.

Conclusions:

  • This study reveals the mechanism of CIC-DUX4-mediated transcriptional activation.
  • The interaction with p300 is key to CIC-DUX4's oncogenic activity in CDS.
  • Pharmacological inhibition of p300 presents a potential therapeutic avenue for CDS patients.
Keywords:
CIC-DUX4ChIP-seqepigeneticsp300sarcoma

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