CIC-DUX4 chromatin profiling reveals new epigenetic dependencies and actionable therapeutic targets in CIC-rearranged sarcomas

Article Article scientifique Article CIC-DUX4 chromatin profiling reveals new epigenetic dependencies and actionable therapeutic targets in CIC-rearranged sarcomas eng 2024-01-21 2024-01-21 author Bakaric Arnaud 0000-0001-6784-7060 Clinical Pathology Service, Department of Diagnostics, Geneva University Hospital, 1205 Geneva, Switzerland. 955044 Département de médecine génétique et développement (GEDEV) author Cironi Luisa Pediatric Hematology-Oncology Research Laboratory, Woman-Mother-Child Department, Lausanne University Hospital, University of Lausanne, 1011 Lausanne, Switzerland. author Praz Viviane Platform Genomics Technologies, Center for Integrative Genomics, Faculty of Biology and Medicine, Lausanne University Hospital, University of Lausanne, 1011 Lausanne, Switzerland. 43702 author Sanalkumar Rajendran 0000-0002-4981-4449 Experimental Pathology Service, Lausanne University Hospital, University of Lausanne, 1011 Lausanne, Switzerland.,Department of Cell and Tissue Genomics, Genentech. Inc., South San Francisco, CA 94103, USA. author Broye Liliane C Experimental Pathology Service, Lausanne University Hospital, University of Lausanne, 1011 Lausanne, Switzerland. author Favre-Bulle Kerria Experimental Pathology Service, Lausanne University Hospital, University of Lausanne, 1011 Lausanne, Switzerland. author Letovanec Igor Department of Histopathology, Central Institute, Valais Hospital, 1951 Sion, Switzerland. 591736 author Digklia Antonia 0000-0001-7189-3035 Department of Oncology, Lausanne University Hospital, University of Lausanne, 1011 Lausanne, Switzerland. author Renella Raffaele Pediatric Hematology-Oncology Research Laboratory, Woman-Mother-Child Department, Lausanne University Hospital, University of Lausanne, 1011 Lausanne, Switzerland. 105990 author Stamenkovic Ivan Experimental Pathology Service, Lausanne University Hospital, University of Lausanne, 1011 Lausanne, Switzerland. author Ott Christopher J Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA.,Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.,Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. author Nakamura Takuro 0000-0002-0419-7547 Institute of Medical Science, Tokyo Medical University, Tokyo 160-0023, Japan. author Antonescu Cristina R Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. author Rivera Miguel N Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA.,Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. author Riggi Nicolo Experimental Pathology Service, Lausanne University Hospital, University of Lausanne, 1011 Lausanne, Switzerland.,Department of Cell and Tissue Genomics, Genentech. Inc., South San Francisco, CA 94103, USA. 105061 457 10.3390/cancers16020457 38275898 2072-6694 PMC10814785 https://www.mdpi.com/2072-6694/16/2/457 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. CIC-DUX4 ChIP-seq Epigenetics P300 Sarcoma Dewey 616.07 137 Département de pathologie et immunologie 21F false https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE248117 https://zenodo.org/records/10141898 Cancers 16 2 bac7ea48-132d-4cb1-9750-764b7943e83a Article (Published version) Public Article-scientifique-from-europePmc.pdf 8993666 application/pdf CC BY-4.0 af956c9e0b8cf9a6d5d152306e7f6f183416099fb44e3ee210e672d22724e6e8 4b60cf07-4b6a-46cd-8323-7147babf7716 Supplemental data Public cancers-2782420-supplementary.pdf 1502935 application/pdf 6d9652bb95c14914f6d4517af438886dc0d818193645bb68731c2efcafa27d36 openAccess Faculté de médecine / Section de médecine fondamentale / Département de pathologie et immunologie

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CIC-DUX4 chromatin profiling reveals new epigenetic dependencies and actionable therapeutic targets in CIC-rearranged sarcomas	Cancers			2024	91	205

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