Journal
CANCER CELL
Volume 33, Issue 3, Pages 527-+Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2018.01.018
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Funding
- EMBO long-term fellowship
- NIH [4P01CA013106-45]
- Comprehensive Cancer Support grant [P30 CA00848-49]
- Liddy Shriver Sarcoma Initiative [20R20987]
- Canadian Cancer Society Research Institute [701582]
- Terry Fox Research Institute [TFF 105265]
- Christina Renna Foundation
- Clark Gillies Foundation
- Friends of T.J. Foundation
- Michelle Paternoster Foundation
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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 de-regulates developmental programs to drive transformation by hijacking a transcriptional repressive complex to aberrantly activate gene expression.
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