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Published on: October 2, 2017

BRD9 Degraders Unleash GBAF Chromatin Remodeling Activity in Synovial Sarcoma

Jinxiu Li1, Mary L Nelson1, Li Li1

  • 1University of Utah Salt Lake City, UT United States.

Cancer Research
|June 26, 2026
PubMed

Insights

Synovial sarcoma cells depend on BRD9, but its depletion paradoxically boosts cancer gene activity. This explains why BRD9 degraders failed in clinical trials for synovial sarcoma (SyS).

Area of Science:

  • Molecular Biology
  • Epigenetics
  • Cancer Research

Background:

  • Synovial sarcoma (SyS) relies on the SS18::SSX oncoprotein within GBAF complexes, creating a dependency on the BRD9 subunit.
  • Clinical trials using BRD9 degraders for SyS have not yielded significant clinical benefits.

Purpose of the Study:

  • To elucidate the mechanistic basis for the limited efficacy of BRD9 degraders in synovial sarcoma.
  • To understand the role of BRD9 in GBAF complex function and its impact on SyS pathogenesis.

Main Methods:

  • Cellular and xenograft models of SyS
  • Biochemical assays with purified GBAF complexes
  • Analysis of GBAF enrichment, chromatin accessibility, and gene transcription upon BRD9 depletion

Main Results:

  • BRD9 depletion did not disrupt GBAF complex assembly but reduced its enrichment at target loci.
  • In the absence of BRD9, GBAF complexes maintained or increased chromatin accessibility and gene transcription.
  • Biochemical assays revealed that BRD9 restrains GBAF's nucleosome sliding activity, and its degradation enhances this remodeling.

Conclusions:

  • BRD9 acts as a brake on GBAF enzymatic activity; its degradation unleashes increased chromatin remodeling and gene expression in SyS.
  • This enhanced epigenetic activity presents a low-level challenge for SyS, explaining the limited therapeutic success of BRD9 degraders.

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