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

Ana Banito, Xiang Li, Aimée N. Laporte, Jae Seok Roe, Francisco Sanchez-Vega, Chun Hao Huang, Amanda R. Dancsok, Katerina Hatzi, Chi Chao Chen, Darjus F. Tschaharganeh, Rohit Chandwani, Nilgun Tasdemir, Kevin B. Jones, Mario R. Capecchi, Christopher R. Vakoc, Nikolaus Schultz, Marc Ladanyi, Torsten O. Nielsen, Scott W. Lowe

Research output: Contribution to journalArticle

22 Citations (Scopus)

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. 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.

Original languageEnglish
Pages (from-to)527-541.e8
JournalCancer Cell
Volume33
Issue number3
DOIs
Publication statusPublished - 2018 Mar 12

Fingerprint

Synovial Sarcoma
Polycomb Repressive Complex 1
Oncogene Proteins
Histone Demethylases
Genes
Genetic Translocation
CpG Islands
Genomics
Transcription Factors
Gene Expression
Neoplasms

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

Banito, A., Li, X., Laporte, A. N., Roe, J. S., Sanchez-Vega, F., Huang, C. H., ... Lowe, S. W. (2018). The SS18-SSX Oncoprotein Hijacks KDM2B-PRC1.1 to Drive Synovial Sarcoma. Cancer Cell, 33(3), 527-541.e8. https://doi.org/10.1016/j.ccell.2018.01.018
Banito, Ana ; Li, Xiang ; Laporte, Aimée N. ; Roe, Jae Seok ; Sanchez-Vega, Francisco ; Huang, Chun Hao ; Dancsok, Amanda R. ; Hatzi, Katerina ; Chen, Chi Chao ; Tschaharganeh, Darjus F. ; Chandwani, Rohit ; Tasdemir, Nilgun ; Jones, Kevin B. ; Capecchi, Mario R. ; Vakoc, Christopher R. ; Schultz, Nikolaus ; Ladanyi, Marc ; Nielsen, Torsten O. ; Lowe, Scott W. / The SS18-SSX Oncoprotein Hijacks KDM2B-PRC1.1 to Drive Synovial Sarcoma. In: Cancer Cell. 2018 ; Vol. 33, No. 3. pp. 527-541.e8.
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Banito, A, Li, X, Laporte, AN, Roe, JS, Sanchez-Vega, F, Huang, CH, Dancsok, AR, Hatzi, K, Chen, CC, Tschaharganeh, DF, Chandwani, R, Tasdemir, N, Jones, KB, Capecchi, MR, Vakoc, CR, Schultz, N, Ladanyi, M, Nielsen, TO & Lowe, SW 2018, 'The SS18-SSX Oncoprotein Hijacks KDM2B-PRC1.1 to Drive Synovial Sarcoma', Cancer Cell, vol. 33, no. 3, pp. 527-541.e8. https://doi.org/10.1016/j.ccell.2018.01.018

The SS18-SSX Oncoprotein Hijacks KDM2B-PRC1.1 to Drive Synovial Sarcoma. / Banito, Ana; Li, Xiang; Laporte, Aimée N.; Roe, Jae Seok; Sanchez-Vega, Francisco; Huang, Chun Hao; Dancsok, Amanda R.; Hatzi, Katerina; Chen, Chi Chao; Tschaharganeh, Darjus F.; Chandwani, Rohit; Tasdemir, Nilgun; Jones, Kevin B.; Capecchi, Mario R.; Vakoc, Christopher R.; Schultz, Nikolaus; Ladanyi, Marc; Nielsen, Torsten O.; Lowe, Scott W.

In: Cancer Cell, Vol. 33, No. 3, 12.03.2018, p. 527-541.e8.

Research output: Contribution to journalArticle

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AU - Banito, Ana

AU - Li, Xiang

AU - Laporte, Aimée N.

AU - Roe, Jae Seok

AU - Sanchez-Vega, Francisco

AU - Huang, Chun Hao

AU - Dancsok, Amanda R.

AU - Hatzi, Katerina

AU - Chen, Chi Chao

AU - Tschaharganeh, Darjus F.

AU - Chandwani, Rohit

AU - Tasdemir, Nilgun

AU - Jones, Kevin B.

AU - Capecchi, Mario R.

AU - Vakoc, Christopher R.

AU - Schultz, Nikolaus

AU - Ladanyi, Marc

AU - Nielsen, Torsten O.

AU - Lowe, Scott W.

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N2 - 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.

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Banito A, Li X, Laporte AN, Roe JS, Sanchez-Vega F, Huang CH et al. The SS18-SSX Oncoprotein Hijacks KDM2B-PRC1.1 to Drive Synovial Sarcoma. Cancer Cell. 2018 Mar 12;33(3):527-541.e8. https://doi.org/10.1016/j.ccell.2018.01.018