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NSD1 mediates antagonism between SWI/SNF and polycomb complexes and is required for transcriptional activation upon

Yiannis Drosos1, Jacquelyn A Myers1, Beisi Xu2

  • 1Division of Molecular Oncology, Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA.

Molecular Cell
|May 10, 2022
PubMed

Insights

Loss of NSD1 disrupts the balance between SWI/SNF and polycomb complexes, causing resistance to EZH2 inhibitors in cancer. Restoring H3K36me2 levels re-sensitizes cells to EZH2 inhibition.

Area of Science:

  • Cancer Biology
  • Epigenetics
  • Chromatin Remodeling

Background:

  • Disruption of SWI/SNF chromatin remodelers and polycomb repressor complexes contributes to various cancers.
  • EZH2 inhibitors are approved for SMARCB1-mutant sarcoma, but resistance is a challenge.

Purpose of the Study:

  • Identify genetic factors in SWI/SNF-polycomb antagonism and EZH2 inhibitor resistance.
  • Elucidate the role of NSD1 in SWI/SNF-polycomb interplay and cancer development.

Main Methods:

  • CRISPR screens in SMARCB1-mutant rhabdoid tumor cells.
  • Assays to assess EZH2 inhibition efficacy and H3K36me2 levels.
  • Analysis of co-occurrence of NSD1 inactivation in SWI/SNF-defective cancers.

Main Results:

  • Loss of NSD1 confers resistance to EZH2 inhibition by disrupting SWI/SNF-polycomb antagonism.
  • NSD1 inactivation is found in SWI/SNF-defective cancers, suggesting in vivo relevance.
  • Inhibition of KDM2A restores EZH2 inhibitor efficacy in NSD1-deficient cells by modulating H3K36me2.

Conclusions:

  • NSD1 is a key regulator of the SWI/SNF-polycomb axis and a determinant of EZH2 inhibitor response.
  • Targeting H3K36me2 demethylases may overcome resistance to EZH2 inhibitors in SWI/SNF-mutant cancers.
Keywords:
BAFEZH2 inhibitionNSD1SWI/SNFchromatinepigeneticspolycombtranscription

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