A Non-Canonical SWI/SNF Complex Is a Synthetic Lethal Target in Cancers Driven by BAF Complex Perturbation

Nat Cell Biol. 2018 Dec;20(12):1410-1420. doi: 10.1038/s41556-018-0221-1. Epub 2018 Nov 5.

Abstract

Mammalian SWI/SNF chromatin remodelling complexes exist in three distinct, final-form assemblies: canonical BAF (cBAF), PBAF and a newly characterized non-canonical complex (ncBAF). However, their complex-specific targeting on chromatin, functions and roles in disease remain largely undefined. Here, we comprehensively mapped complex assemblies on chromatin and found that ncBAF complexes uniquely localize to CTCF sites and promoters. We identified ncBAF subunits as synthetic lethal targets specific to synovial sarcoma and malignant rhabdoid tumours, which both exhibit cBAF complex (SMARCB1 subunit) perturbation. Chemical and biological depletion of the ncBAF subunit, BRD9, rapidly attenuates synovial sarcoma and malignant rhabdoid tumour cell proliferation. Importantly, in cBAF-perturbed cancers, ncBAF complexes maintain gene expression at retained CTCF-promoter sites and function in a manner distinct from fusion oncoprotein-bound complexes. Together, these findings unmask the unique targeting and functional roles of ncBAF complexes and present new cancer-specific therapeutic targets.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Chromatin / genetics*
  • Chromatin / metabolism
  • Chromatin Assembly and Disassembly / genetics
  • Chromosomal Proteins, Non-Histone / genetics*
  • Chromosomal Proteins, Non-Histone / metabolism
  • HEK293 Cells
  • Humans
  • Mutation
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Promoter Regions, Genetic / genetics
  • RNA Interference
  • Rhabdoid Tumor / genetics*
  • Rhabdoid Tumor / metabolism
  • Sarcoma, Synovial / genetics*
  • Sarcoma, Synovial / metabolism
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism

Substances

  • BRD9 protein, human
  • Chromatin
  • Chromosomal Proteins, Non-Histone
  • Nuclear Proteins
  • SWI-SNF-B chromatin-remodeling complex
  • Transcription Factors