The SS18-SSX Fusion Oncoprotein Hijacks BAF Complex Targeting and Function to Drive Synovial Sarcoma. - Literature - Data resources

29861296

The SS18-SSX Fusion Oncoprotein Hijacks BAF Complex Targeting and Function to Drive Synovial Sarcoma.

Cancer Cell, 2018/06/11;33(6):1128-1141.e7.

McBride MJ^[1], Pulice JL^[2], Beird HC^[3], Ingram DR^[4], D'Avino AR^[2], Shern JF^[5], Charville GW^[6], Hornick JL^[7], Nakayama RT^[8], Garcia-Rivera EM^[2], Araujo DM^[9], Wang WL^[4], Tsai JW^[4], Yeagley M^[9], Wagner AJ^[10], Futreal PA^[3], Khan J^[5], Lazar AJ^[11], Kadoch C^[12]

Affiliations

Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215, USA; Epigenomics Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Program in Chemical Biology, Harvard University, Cambridge, MA, USA.
Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215, USA; Epigenomics Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Department of Genomic Medicine, MD Anderson Cancer Center, Houston, TX, USA.
Department of Pathology, MD Anderson Cancer Center, Houston, TX, USA; Department of Translational Molecular Pathology, MD Anderson Cancer Center, Houston, TX, USA.
Pediatric Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD, USA.
Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215, USA; Ludwig Center at Dana-Farber/Harvard and Center for Sarcoma and Bone Oncology, Department of Medical Oncology, Harvard Medical School, Boston, MA, USA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
Department of Sarcoma Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
Department of Genomic Medicine, MD Anderson Cancer Center, Houston, TX, USA; Department of Pathology, MD Anderson Cancer Center, Houston, TX, USA; Department of Translational Molecular Pathology, MD Anderson Cancer Center, Houston, TX, USA.
Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215, USA; Epigenomics Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address: cigall_kadoch@dfci.harvard.edu.

PMID: 29861296DOI: 10.1016/j.ccell.2018.05.002

Impact factor: 38.585

Abstract

Synovial sarcoma (SS) is defined by the hallmark SS18-SSX fusion oncoprotein, which renders BAF complexes aberrant in two manners: gain of SSX to the SS18 subunit and concomitant loss of BAF47 subunit assembly. Here we demonstrate that SS18-SSX globally hijacks BAF complexes on chromatin to activate an SS transcriptional signature that we define using primary tumors and cell lines. Specifically, SS18-SSX retargets BAF complexes from enhancers to broad polycomb domains to oppose PRC2-mediated repression and activate bivalent genes. Upon suppression of SS18-SSX, reassembly of BAF47 restores enhancer activation, but is not required for proliferative arrest. These results establish a global hijacking mechanism for SS18-SSX on chromatin, and define the distinct contributions of two concurrent BAF complex perturbations.

Keywords: ATP-dependent chromatin remodeling; SWI/SNF (BAF) complexes; bivalency; chromatin; enhancers; fusion oncoprotein; pediatric cancer; polycomb; synovial sarcoma

MeSH terms

Cell Line, Tumor; Chromatin; Enhancer Elements, Genetic; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; HEK293 Cells; Humans; Oncogene Proteins, Fusion; SMARCB1 Protein; Sarcoma, Synovial; Exome Sequencing

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