The SS18-SSX Fusion Oncoprotein Hijacks BAF Complex Targeting and Function to Drive Synovial Sarcoma

Matthew J. McBride, John L. Pulice, Hannah C. Beird, Davis R. Ingram, Andrew R. D'Avino, Jack F. Shern, Gregory W. Charville, Jason L. Hornick, Turrent Robert Nakayama, Enrique M. Garcia-Rivera, Dejka M. Araujo, Wei Lien Wang, Jen Wei Tsai, Michelle Yeagley, Andrew J. Wagner, P. Andrew Futreal, Javed Khan, Alexander J. Lazar, Cigall Kadoch

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Synovial sarcoma (SS) is defined by the hallmark SS18-SSX fusion oncoprotein, which renders BAF complexes aberrant in two manners: gain of SSX to the SS18 subunit and concomitant loss of BAF47 subunit assembly. Here we demonstrate that SS18-SSX globally hijacks BAF complexes on chromatin to activate an SS transcriptional signature that we define using primary tumors and cell lines. Specifically, SS18-SSX retargets BAF complexes from enhancers to broad polycomb domains to oppose PRC2-mediated repression and activate bivalent genes. Upon suppression of SS18-SSX, reassembly of BAF47 restores enhancer activation, but is not required for proliferative arrest. These results establish a global hijacking mechanism for SS18-SSX on chromatin, and define the distinct contributions of two concurrent BAF complex perturbations. Incorporation of the synovial sarcoma SS18-SSX fusion into BAF complexes results in concomitant eviction of BAF47. McBride et al. show that SS18-SSX retargets BAF complexes from enhancers to polycomb domains to oppose PRC2-mediated repression. Reincorporation of BAF47 upon suppression of SS18-SSX restores enhancer activation but is not required for proliferative arrest.

Original languageEnglish
JournalCancer Cell
DOIs
Publication statusAccepted/In press - 2018 Jan 1
Externally publishedYes

Fingerprint

Synovial Sarcoma
Oncogene Proteins
Chromatin
Tumor Cell Line
Genes

Keywords

  • ATP-dependent chromatin remodeling
  • bivalency
  • chromatin
  • enhancers
  • fusion oncoprotein
  • pediatric cancer
  • polycomb
  • SWI/SNF (BAF) complexes
  • synovial sarcoma

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

McBride, M. J., Pulice, J. L., Beird, H. C., Ingram, D. R., D'Avino, A. R., Shern, J. F., ... Kadoch, C. (Accepted/In press). The SS18-SSX Fusion Oncoprotein Hijacks BAF Complex Targeting and Function to Drive Synovial Sarcoma. Cancer Cell. https://doi.org/10.1016/j.ccell.2018.05.002

The SS18-SSX Fusion Oncoprotein Hijacks BAF Complex Targeting and Function to Drive Synovial Sarcoma. / McBride, Matthew J.; Pulice, John L.; Beird, Hannah C.; Ingram, Davis R.; D'Avino, Andrew R.; Shern, Jack F.; Charville, Gregory W.; Hornick, Jason L.; Nakayama, Turrent Robert; Garcia-Rivera, Enrique M.; Araujo, Dejka M.; Wang, Wei Lien; Tsai, Jen Wei; Yeagley, Michelle; Wagner, Andrew J.; Futreal, P. Andrew; Khan, Javed; Lazar, Alexander J.; Kadoch, Cigall.

In: Cancer Cell, 01.01.2018.

Research output: Contribution to journalArticle

McBride, MJ, Pulice, JL, Beird, HC, Ingram, DR, D'Avino, AR, Shern, JF, Charville, GW, Hornick, JL, Nakayama, TR, Garcia-Rivera, EM, Araujo, DM, Wang, WL, Tsai, JW, Yeagley, M, Wagner, AJ, Futreal, PA, Khan, J, Lazar, AJ & Kadoch, C 2018, 'The SS18-SSX Fusion Oncoprotein Hijacks BAF Complex Targeting and Function to Drive Synovial Sarcoma', Cancer Cell. https://doi.org/10.1016/j.ccell.2018.05.002
McBride, Matthew J. ; Pulice, John L. ; Beird, Hannah C. ; Ingram, Davis R. ; D'Avino, Andrew R. ; Shern, Jack F. ; Charville, Gregory W. ; Hornick, Jason L. ; Nakayama, Turrent Robert ; Garcia-Rivera, Enrique M. ; Araujo, Dejka M. ; Wang, Wei Lien ; Tsai, Jen Wei ; Yeagley, Michelle ; Wagner, Andrew J. ; Futreal, P. Andrew ; Khan, Javed ; Lazar, Alexander J. ; Kadoch, Cigall. / The SS18-SSX Fusion Oncoprotein Hijacks BAF Complex Targeting and Function to Drive Synovial Sarcoma. In: Cancer Cell. 2018.
@article{a2123ca590c04b4d8052a3745a3466e3,
title = "The SS18-SSX Fusion Oncoprotein Hijacks BAF Complex Targeting and Function to Drive Synovial Sarcoma",
abstract = "Synovial sarcoma (SS) is defined by the hallmark SS18-SSX fusion oncoprotein, which renders BAF complexes aberrant in two manners: gain of SSX to the SS18 subunit and concomitant loss of BAF47 subunit assembly. Here we demonstrate that SS18-SSX globally hijacks BAF complexes on chromatin to activate an SS transcriptional signature that we define using primary tumors and cell lines. Specifically, SS18-SSX retargets BAF complexes from enhancers to broad polycomb domains to oppose PRC2-mediated repression and activate bivalent genes. Upon suppression of SS18-SSX, reassembly of BAF47 restores enhancer activation, but is not required for proliferative arrest. These results establish a global hijacking mechanism for SS18-SSX on chromatin, and define the distinct contributions of two concurrent BAF complex perturbations. Incorporation of the synovial sarcoma SS18-SSX fusion into BAF complexes results in concomitant eviction of BAF47. McBride et al. show that SS18-SSX retargets BAF complexes from enhancers to polycomb domains to oppose PRC2-mediated repression. Reincorporation of BAF47 upon suppression of SS18-SSX restores enhancer activation but is not required for proliferative arrest.",
keywords = "ATP-dependent chromatin remodeling, bivalency, chromatin, enhancers, fusion oncoprotein, pediatric cancer, polycomb, SWI/SNF (BAF) complexes, synovial sarcoma",
author = "McBride, {Matthew J.} and Pulice, {John L.} and Beird, {Hannah C.} and Ingram, {Davis R.} and D'Avino, {Andrew R.} and Shern, {Jack F.} and Charville, {Gregory W.} and Hornick, {Jason L.} and Nakayama, {Turrent Robert} and Garcia-Rivera, {Enrique M.} and Araujo, {Dejka M.} and Wang, {Wei Lien} and Tsai, {Jen Wei} and Michelle Yeagley and Wagner, {Andrew J.} and Futreal, {P. Andrew} and Javed Khan and Lazar, {Alexander J.} and Cigall Kadoch",
year = "2018",
month = "1",
day = "1",
doi = "10.1016/j.ccell.2018.05.002",
language = "English",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",

}

TY - JOUR

T1 - The SS18-SSX Fusion Oncoprotein Hijacks BAF Complex Targeting and Function to Drive Synovial Sarcoma

AU - McBride, Matthew J.

AU - Pulice, John L.

AU - Beird, Hannah C.

AU - Ingram, Davis R.

AU - D'Avino, Andrew R.

AU - Shern, Jack F.

AU - Charville, Gregory W.

AU - Hornick, Jason L.

AU - Nakayama, Turrent Robert

AU - Garcia-Rivera, Enrique M.

AU - Araujo, Dejka M.

AU - Wang, Wei Lien

AU - Tsai, Jen Wei

AU - Yeagley, Michelle

AU - Wagner, Andrew J.

AU - Futreal, P. Andrew

AU - Khan, Javed

AU - Lazar, Alexander J.

AU - Kadoch, Cigall

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Synovial sarcoma (SS) is defined by the hallmark SS18-SSX fusion oncoprotein, which renders BAF complexes aberrant in two manners: gain of SSX to the SS18 subunit and concomitant loss of BAF47 subunit assembly. Here we demonstrate that SS18-SSX globally hijacks BAF complexes on chromatin to activate an SS transcriptional signature that we define using primary tumors and cell lines. Specifically, SS18-SSX retargets BAF complexes from enhancers to broad polycomb domains to oppose PRC2-mediated repression and activate bivalent genes. Upon suppression of SS18-SSX, reassembly of BAF47 restores enhancer activation, but is not required for proliferative arrest. These results establish a global hijacking mechanism for SS18-SSX on chromatin, and define the distinct contributions of two concurrent BAF complex perturbations. Incorporation of the synovial sarcoma SS18-SSX fusion into BAF complexes results in concomitant eviction of BAF47. McBride et al. show that SS18-SSX retargets BAF complexes from enhancers to polycomb domains to oppose PRC2-mediated repression. Reincorporation of BAF47 upon suppression of SS18-SSX restores enhancer activation but is not required for proliferative arrest.

AB - Synovial sarcoma (SS) is defined by the hallmark SS18-SSX fusion oncoprotein, which renders BAF complexes aberrant in two manners: gain of SSX to the SS18 subunit and concomitant loss of BAF47 subunit assembly. Here we demonstrate that SS18-SSX globally hijacks BAF complexes on chromatin to activate an SS transcriptional signature that we define using primary tumors and cell lines. Specifically, SS18-SSX retargets BAF complexes from enhancers to broad polycomb domains to oppose PRC2-mediated repression and activate bivalent genes. Upon suppression of SS18-SSX, reassembly of BAF47 restores enhancer activation, but is not required for proliferative arrest. These results establish a global hijacking mechanism for SS18-SSX on chromatin, and define the distinct contributions of two concurrent BAF complex perturbations. Incorporation of the synovial sarcoma SS18-SSX fusion into BAF complexes results in concomitant eviction of BAF47. McBride et al. show that SS18-SSX retargets BAF complexes from enhancers to polycomb domains to oppose PRC2-mediated repression. Reincorporation of BAF47 upon suppression of SS18-SSX restores enhancer activation but is not required for proliferative arrest.

KW - ATP-dependent chromatin remodeling

KW - bivalency

KW - chromatin

KW - enhancers

KW - fusion oncoprotein

KW - pediatric cancer

KW - polycomb

KW - SWI/SNF (BAF) complexes

KW - synovial sarcoma

UR - http://www.scopus.com/inward/record.url?scp=85047363222&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85047363222&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2018.05.002

DO - 10.1016/j.ccell.2018.05.002

M3 - Article

C2 - 29861296

AN - SCOPUS:85047363222

JO - Cancer Cell

JF - Cancer Cell

SN - 1535-6108

ER -