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A Role for SMARCB1 in Synovial Sarcomagenesis Reveals That SS18-SSX Induces Canonical BAF Destruction.

Jinxiu Li | Timothy S Mulvihill | Li Li | Jared J Barrott | Mary L Nelson | Lena Wagner | Ian C Lock | Amir Pozner | Sydney Lynn Lambert | Benjamin B Ozenberger | Michael B Ward | Allie H Grossmann | Ting Liu | Ana Banito | Bradley R Cairns | Kevin B Jones
Cancer discovery | 2021

Reduced protein levels of SMARCB1 (also known as BAF47, INI1, SNF5) have long been observed in synovial sarcoma. Here, we show that combined Smarcb1 genetic loss with SS18-SSX expression in mice synergized to produce aggressive tumors with histomorphology, transcriptomes, and genome-wide BAF-family complex distributions distinct from SS18-SSX alone, indicating a defining role for SMARCB1 in synovial sarcoma. Smarcb1 silencing alone in mesenchyme modeled epithelioid sarcomagenesis. In mouse and human synovial sarcoma cells, SMARCB1 was identified within PBAF and canonical BAF (CBAF) complexes, coincorporated with SS18-SSX in the latter. Recombinant expression of CBAF components in human cells reconstituted CBAF subcomplexes that contained equal levels of SMARCB1 regardless of SS18 or SS18-SSX inclusion. In vivo, SS18-SSX expression led to whole-complex CBAF degradation, rendering increases in the relative prevalence of other BAF-family subtypes, PBAF and GBAF complexes, over time. Thus, SS18-SSX alters BAF subtypes levels/balance and genome distribution, driving synovial sarcomagenesis. SIGNIFICANCE: The protein level of BAF component SMARCB1 is reduced in synovial sarcoma but plays a defining role, incorporating into PBAF and SS18-SSX-containing canonical BAF complexes. Reduced levels of SMARCB1 derive from whole-complex degradation of canonical BAF driven by SS18-SSX, with relative increases in the abundance of other BAF-family subtypes.See related commentary by Maxwell and Hargreaves, p. 2375.This article is highlighted in the In This Issue feature, p. 2355.

Pubmed ID: 34078620

Associated grants

  • Agency: NCI NIH HHS, United States
    Id: F30 CA225163
  • Agency: NCI NIH HHS, United States
    Id: P30 CA042014
  • Agency: NCI NIH HHS, United States
    Id: R01 CA201396
  • Agency: NCI NIH HHS, United States
    Id: U54 CA231652

Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.

This is a list of tools and resources that we have found mentioned in this publication.


ChIP-seq (tool)

RRID:SCR_001237

Set of software modules for performing common ChIP-seq data analysis tasks across the whole genome, including positional correlation analysis, peak detection, and genome partitioning into signal-rich and signal-poor regions. The tools are designed to be simple, fast and highly modular. Each program carries out a well defined data processing procedure that can potentially fit into a pipeline framework. ChIP-Seq is also freely available on a Web interface.

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HEK293T (tool)

RRID:CVCL_0063

Cell line HEK293T is a Transformed cell line with a species of origin Homo sapiens (Human)

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Goat Anti-Rabbit IgG (H + L)-HRP Conjugate (antibody)

RRID:AB_11125142

This polyclonal secondary targets IgG (H+L)

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ARID1B antibody (antibody)

RRID:AB_2243092

This monoclonal targets ARID1B

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BAF57/SMARCE1 Antibody (antibody)

RRID:AB_577243

This unknown targets BAF57/SMARCE1

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SMARCC1 Polyclonal Antibody (antibody)

RRID:AB_2547648

This unknown targets SMARCC1

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ARID1A/BAF250A (D2A8U) Rabbit mAb #12354 (antibody)

RRID:AB_2637010

This monoclonal targets ARID1A/BAF250A

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ARID1A/BAF250 Antibody (antibody)

RRID:AB_2060365

This unknown targets ARID1A/BAF250

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BRD7 antibody (antibody)

RRID:AB_2259226

This polyclonal targets BRD7

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PB1/BAF180 Antibody (antibody)

RRID:AB_1078808

This unknown targets PBRM1

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SMARCC2-human (antibody)

RRID:AB_2192014

This polyclonal targets SMARCC2

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V5-Probe (G-14) (antibody)

RRID:AB_2019670

This monoclonal targets V5-Probe (G-14)

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BRG1 antibody [EPNCIR111A] (antibody)

RRID:AB_10861578

This monoclonal targets BRG1 antibody [EPNCIR111A]

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SS18/SSX Antibody (antibody)

RRID:AB_2799794

This unknown targets SS18/SSX1 fusion

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H3-celegans (antibody)

RRID:AB_302613

This polyclonal targets H3

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Anti-HA EPITOPE TAG (RABBIT) Antibody - 600-401-384 (antibody)

RRID:AB_217929

This polyclonal targets HA EPITOPE TAG Antibody

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Anti-DPF2 antibody (antibody)

RRID:AB_2728668

This monoclonal targets DPF2

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RNA polymerase II CTD repeat YSPTSPS (phospho S5) antibody - ChIP Grade (antibody)

RRID:AB_449369

This polyclonal targets RNA polymerase II CTD repeat YSPTSPS (phospho S5) antibody - ChIP Grade

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SMARCC1 antibody (antibody)

RRID:AB_2191987

This polyclonal targets SMARCC1

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Goat Anti-Mouse IgG (H L)-HRP Conjugate (antibody)

RRID:AB_11125547

This unknown targets Goat Mouse IgG (H L)-HRP Conjugate

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SMARCB1/SNF5 Antibody (antibody)

RRID:AB_2191714

This unknown targets SMARCB1/SNF5

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IRDye 800CW Goat anti-Rabbit IgG (antibody)

RRID:AB_621843

This polyclonal secondary targets IgG

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SS18 (D6I4Z) (antibody)

RRID:AB_2728667

This monoclonal targets SS18

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