2. Academic Validation
  3. CIC-DUX4 Chromatin Profiling Reveals New Epigenetic Dependencies and Actionable Therapeutic Targets in CIC-Rearranged Sarcomas

CIC-DUX4 Chromatin Profiling Reveals New Epigenetic Dependencies and Actionable Therapeutic Targets in CIC-Rearranged Sarcomas

  • Cancers (Basel). 2024 Jan 21;16(2):457. doi: 10.3390/cancers16020457.
Arnaud Bakaric 1,  Luisa Cironi 2,  Viviane Praz 3,  Rajendran Sanalkumar 4 5,  Liliane C Broye 4,  Kerria Favre-Bulle 4,  Igor Letovanec 6,  Antonia Digklia 7,  Raffaele Renella 2,  Ivan Stamenkovic 4,  Christopher J Ott 8 9 10,  Takuro Nakamura 11,  Cristina R Antonescu 12,  Miguel N Rivera 8 10,  Nicolò Riggi 4 5
Affiliations

Affiliations

  • 1 Clinical Pathology Service, Department of Diagnostics, Geneva University Hospital, 1205 Geneva, Switzerland.
  • 2 Pediatric Hematology-Oncology Research Laboratory, Woman-Mother-Child Department, Lausanne University Hospital, University of Lausanne, 1011 Lausanne, Switzerland.
  • 3 Platform Genomics Technologies, Center for Integrative Genomics, Faculty of Biology and Medicine, Lausanne University Hospital, University of Lausanne, 1011 Lausanne, Switzerland.
  • 4 Experimental Pathology Service, Lausanne University Hospital, University of Lausanne, 1011 Lausanne, Switzerland.
  • 5 Department of Cell and Tissue Genomics, Genentech. Inc., South San Francisco, CA 94103, USA.
  • 6 Department of Histopathology, Central Institute, Valais Hospital, 1951 Sion, Switzerland.
  • 7 Department of Oncology, Lausanne University Hospital, University of Lausanne, 1011 Lausanne, Switzerland.
  • 8 Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA.
  • 9 Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
  • 10 Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • 11 Institute of Medical Science, Tokyo Medical University, Tokyo 160-0023, Japan.
  • 12 Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
PMID: 38275898 DOI: 10.3390/cancers16020457
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; additionally, we find its pharmacological inhibition to significantly impact tumor growth in vitro and in vivo. Taken together, our study elucidates the mechanisms underpinning CIC-DUX4-mediated transcriptional regulation.

Keywords

CIC-DUX4; ChIP-seq; epigenetics; p300; sarcoma.

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