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A non-canonical SWI/SNF complex is a synthetic lethal target in cancers driven by BAF complex perturbation

Brittany C Michel1,2,3, Andrew R D'Avino1,2, Seth H Cassel1,2,3,4

  • 1Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.

Nature Cell Biology
|November 7, 2018
PubMed

Insights

The non-canonical BAF (ncBAF) chromatin remodeler targets CTCF sites and promoters. Depleting ncBAF subunits, like BRD9, halts cancer growth, revealing ncBAF as a novel therapeutic target in specific cancers.

Area of Science:

  • Chromatin biology
  • Molecular oncology
  • Epigenetics

Background:

  • Mammalian SWI/SNF complexes are key chromatin remodelers, with known subtypes including canonical BAF (cBAF) and PBAF.
  • A distinct non-canonical BAF (ncBAF) complex has been identified, but its specific functions and disease relevance are unclear.

Purpose of the Study:

  • To define the unique chromatin localization, functions, and disease-specific roles of ncBAF complexes.
  • To investigate ncBAF complexes as potential therapeutic targets in cancers with SWI/SNF pathway alterations.

Main Methods:

  • Comprehensive chromatin mapping of SWI/SNF complex assemblies.
  • Functional assays involving chemical and biological depletion of ncBAF subunits (e.g., BRD9).
  • Analysis of ncBAF function in cancers with canonical BAF (cBAF) complex perturbations, specifically SMARCB1-deficient tumors.

Main Results:

  • ncBAF complexes uniquely localize to CTCF sites and promoters.
  • ncBAF subunits were identified as synthetic lethal targets in synovial sarcoma and malignant rhabdoid tumors (MRT).
  • Depletion of BRD9 in ncBAF complexes rapidly inhibited proliferation in synovial sarcoma and MRT cell lines.
  • ncBAF complexes maintain gene expression at CTCF-promoter sites in cBAF-perturbed cancers, functioning distinctly from oncoprotein-bound complexes.

Conclusions:

  • ncBAF complexes possess unique chromatin targeting and functional roles distinct from other SWI/SNF assemblies.
  • ncBAF complexes represent promising, cancer-specific therapeutic targets, particularly for synovial sarcoma and MRT.
  • Targeting ncBAF offers a novel strategy for treating cancers with SMARCB1 perturbations.

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