Format

Send to

Choose Destination
Cancer Cell. 2018 Jun 11;33(6):1128-1141.e7. doi: 10.1016/j.ccell.2018.05.002. Epub 2018 May 31.

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

Author information

1
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.
2
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.
3
Department of Genomic Medicine, MD Anderson Cancer Center, Houston, TX, USA.
4
Department of Pathology, MD Anderson Cancer Center, Houston, TX, USA; Department of Translational Molecular Pathology, MD Anderson Cancer Center, Houston, TX, USA.
5
Pediatric Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD, USA.
6
Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
7
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
8
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.
9
Department of Sarcoma Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA.
10
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
11
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.
12
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.

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

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center