Format

Send to

Choose Destination
Cancer Cell. 2018 Mar 12;33(3):527-541.e8. doi: 10.1016/j.ccell.2018.01.018. Epub 2018 Mar 1.

The SS18-SSX Oncoprotein Hijacks KDM2B-PRC1.1 to Drive Synovial Sarcoma.

Author information

1
Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
2
Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA; Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA.
3
Department of Pathology and Laboratory Medicine, Vancouver Coastal Health Research Institute and Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
4
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
5
Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
6
Department of Orthopedics and Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 84103, USA.
7
Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
8
Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA; Howard Hughes Medical Institute, New York, NY 10065, USA. Electronic address: lowes@mskcc.org.

Abstract

Synovial sarcoma is an aggressive cancer invariably associated with a chromosomal translocation involving genes encoding the SWI-SNF complex component SS18 and an SSX (SSX1 or SSX2) transcriptional repressor. Using functional genomics, we identify KDM2B, a histone demethylase and component of a non-canonical polycomb repressive complex 1 (PRC1.1), as selectively required for sustaining synovial sarcoma cell transformation. SS18-SSX1 physically interacts with PRC1.1 and co-associates with SWI/SNF and KDM2B complexes on unmethylated CpG islands. Via KDM2B, SS18-SSX1 binds and aberrantly activates expression of developmentally regulated genes otherwise targets of polycomb-mediated repression, which is restored upon KDM2B depletion, leading to irreversible mesenchymal differentiation. Thus, SS18-SSX1 deregulates developmental programs to drive transformation by hijacking a transcriptional repressive complex to aberrantly activate gene expression.

KEYWORDS:

CRISPR/Cas9-mediated endogenous protein tagging; DNA methylation; SWI/SNF; epigenetics; non-canonical polycomb repressive complex; oncogenic gene fusion; sarcoma

PMID:
29502955
PMCID:
PMC5881394
DOI:
10.1016/j.ccell.2018.01.018
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center