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. Banito et al. show that SS18-SSX fusions characteristic of synovial sarcoma associate with KDM2B-PRC1.1, a non-canonical polycomb repressive complex 1, to aberrantly activate the expression of developmentally regulated transcription factors that are normally targets of polycomb-mediated gene repression.
Bibliographical noteFunding Information:
The authors are grateful to Charles Sherr, Neal Poulin, and members of the Lowe laboratory for comments and discussions, Amaia Lujambio for help with the analysis of shRNA screening data, Tatsuo Ito and Shinji Kohsaka for human synovial sarcoma cell lines, Alexandros Tzatsos for sharing KDM2B-expressing vectors, and Yilong Zou for help designing the strategy for endogenous HA-tagging. A.B. was supported by an EMBO long-term fellowship. This work was supported by an NIH P01 ( 4P01CA013106-45 ), a Comprehensive Cancer Support grant ( P30 CA00848-49 ), and a project grant from the Liddy Shriver Sarcoma Initiative ( 20R20987 ) (PI, T.O.N.). A.N.L., A.R.D., and T.O.N. were supported by the Canadian Cancer Society Research Institute (grant #701582 ) and the Terry Fox Research Institute (TFF 105265 , New Frontiers in Cancer). C.R.V. and J.-S.R. are supported by The Christina Renna Foundation , The Clark Gillies Foundation , The Friends of T.J. Foundation , and The Michelle Paternoster Foundation . S.W.L. is the Geoffrey Beene chair for Cancer Biology and an Investigator in the Howard Hughes Medical Institute. S.W.L. would like to dedicate this work to Enrique (Henry) Cepero.
All Science Journal Classification (ASJC) codes
- Cell Biology
- Cancer Research