PHIP suppresses NuRD to enable the growth of SWI/SNF-mutant cancers

  • Nat Commun. 2026 Apr 7;17(1):2877. doi: 10.1038/s41467-026-70699-3.
Hayden A Malone  1  2 ,  Jacquelyn A Myers  1 ,  Emma G Gruss  1 ,  Marc A Morgan  1 ,  Jake D Friske  2  3 ,  Tabitha C McCarty  1 ,  John J Navarro  1 ,  Sarah Robinson  3 ,  Rebecca L Halliburton  1 ,  Sandra J Kietlinska  1  2 ,  Francisca N De Luna Vitorino  4 ,  Baranda S Hansen  5 ,  Shondra M Pruett-Miller  5 ,  Benjamin A Garcia  4 ,  Martine F Roussel  2  3 ,  Janet F Partridge  1 ,  Charles W M Roberts  6  7
Affiliations
  • 1. Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • 2. St. Jude Graduate School of Biomedical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • 3. Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • 4. Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, USA.
  • 5. Center for Advanced Genome Engineering, Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • 6. Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA. [email protected].
  • 7. St. Jude Graduate School of Biomedical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA. [email protected].
PMID: 41946722 DOI: 10.1038/s41467-026-70699-3
Abstract

SWI/SNF chromatin remodeling complexes are perturbed in 20% of all cancers and in several developmental disorders, yet the mechanisms by which these mutations dysregulate transcription and drive disease are poorly understood. To both elucidate these mechanisms and identify vulnerabilities caused by these mutations, we leverage genome-wide CRISPR-Cas9 screening in hundreds of Cancer cell lines and identify the chromatin reader protein PHIP as a specific dependency in cancers with broadly disrupted SWI/SNF function. Mechanistically, we reveal that PHIP cooperates with SWI/SNF to facilitate transcriptional activation by ubiquitinating and suppressing subunits of the repressive Nucleosome Remodeling and Deacetylase (NuRD) complex. We demonstrate that loss of SWI/SNF results in NuRD complexes accumulating at promoters where they would otherwise cause widespread transcriptional silencing if not antagonized by PHIP. Collectively, we identify PHIP as a regulator of the interplay between distinct chromatin regulators that function in development and disease and as a targetable vulnerability in cancers with broad SWI/SNF inactivation.

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