Cancer Cell
Volume 33, Issue 3, 12 March 2018, Pages 527-541.e8
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Article
The SS18-SSX Oncoprotein Hijacks KDM2B-PRC1.1 to Drive Synovial Sarcoma

https://doi.org/10.1016/j.ccell.2018.01.018Get rights and content
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Highlights

  • An RNAi screen identifies KDM2B as an epigenetic dependency in synovial sarcoma

  • KDM2B depletion abolishes neurogenic programs inducing mesenchymal differentiation

  • KDM2B-PRC1.1 recruits SS18-SSX and SWI/SNF to unmethylated CpG islands

  • SS18-SSX hijacks a repressive complex to aberrantly activate gene expression

Summary

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

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

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