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Mapping the Structure-Function Relationships of Disordered Oncogenic Transcription Factors Using Transcriptomic Analysis
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Shifted assembly and function of mSWI/SNF family subcomplexes underlie targetable dependencies in dedifferentiated

Jessica D St Laurent1,2,3, Grace D Xu1,2, Alexander W Ying1,2

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

Nature Genetics
|October 20, 2025
PubMed

Insights

Loss of ARID1A/B subunits in endometrial cancer shifts chromatin remodeler complexes, promoting tumor growth. Inhibiting SMARCA4/SMARCA2 ATPases halts cancer cell proliferation and enhances chemotherapy effectiveness.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Epigenetics

Background:

  • Mammalian SWI/SNF (mSWI/SNF) complexes are key chromatin remodelers regulating gene expression.
  • These complexes exist in distinct forms: canonical BRG1-associated factor (cBAF), poly(bromo)-associated BAF (PBAF), and noncanonical BAF (ncBAF).
  • ARID1A and ARID1B subunits are crucial for cBAF assembly and are frequently mutated in aggressive dedifferentiated/undifferentiated endometrial carcinomas (DDEC/UECs).

Purpose of the Study:

  • To investigate the functional consequences of ARID1A/B loss in DDEC/UECs.
  • To explore the therapeutic potential of targeting mSWI/SNF ATPase subunits in these cancers.

Main Methods:

  • Utilized cellular models and primary human tumor samples.
  • Assessed mSWI/SNF complex abundance and chromatin function.
  • Administered clinical-grade SMARCA4 and/or SMARCA2 ATPase inhibitors.
  • Evaluated tumor growth inhibition and synergy with carboplatin chemotherapy.

Main Results:

  • ARID1A/B deficiency leads to cBAF loss, increasing ncBAF and PBAF abundance and function.
  • This shift maintains the oncogenic state in DDEC/UECs.
  • SMARCA4/SMARCA2 ATPase inhibitors significantly reduced DDEC cell proliferation and tumor growth in vivo.
  • Inhibitor treatment synergized with carboplatin, extending survival.

Conclusions:

  • Altered mSWI/SNF complex stoichiometry due to ARID1A/B mutations contributes to DDEC/UEC oncogenesis.
  • Targeting mSWI/SNF ATPase activity with small molecule inhibitors shows therapeutic promise for DDEC/UECs.
  • This therapeutic strategy may also benefit other cancers with cBAF disruption.

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