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

doi:10.1016/j.ccell.2018.01.018

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

Department of Biochemistry

Research output: Contribution to journal › Article › peer-review

72 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 language	English
Pages (from-to)	527-541.e8
Journal	Cancer Cell
Volume	33
Issue number	3
DOIs	https://doi.org/10.1016/j.ccell.2018.01.018
Publication status	Published - 2018 Mar 12

Bibliographical note

Funding 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.

Publisher Copyright:
© 2018 Elsevier Inc.

All Science Journal Classification (ASJC) codes

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ccell.2018.01.018

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Banito, A., Li, X., Laporte, A. N., Roe, J. S., Sanchez-Vega, F., Huang, C. H., Dancsok, A. R., Hatzi, K., Chen, C. C., Tschaharganeh, D. F., Chandwani, R., Tasdemir, N., Jones, K. B., Capecchi, M. R., Vakoc, C. R., Schultz, N., Ladanyi, M., Nielsen, T. O., & 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

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title = "The SS18-SSX Oncoprotein Hijacks KDM2B-PRC1.1 to Drive Synovial Sarcoma",

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.",

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

note = "Funding 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. Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",

year = "2018",

month = mar,

day = "12",

doi = "10.1016/j.ccell.2018.01.018",

language = "English",

volume = "33",

pages = "527--541.e8",

journal = "Cancer Cell",

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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

TY - JOUR

T1 - The SS18-SSX Oncoprotein Hijacks KDM2B-PRC1.1 to Drive Synovial Sarcoma

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.

N1 - Funding 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. Publisher Copyright: © 2018 Elsevier Inc.

PY - 2018/3/12

Y1 - 2018/3/12

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.

AB - 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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DO - 10.1016/j.ccell.2018.01.018

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SP - 527-541.e8

JO - Cancer Cell

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

Abstract

Bibliographical note

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UN SDGs

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