2. Academic Validation
  3. Targeting DCAF5 suppresses SMARCB1-mutant cancer by stabilizing SWI/SNF

Targeting DCAF5 suppresses SMARCB1-mutant cancer by stabilizing SWI/SNF

  • Nature. 2024 Mar 27. doi: 10.1038/s41586-024-07250-1.
Sandi Radko-Juettner # 1 2,  Hong Yue # 3 4,  Jacquelyn A Myers 1,  Raymond D Carter 1,  Alexis N Robertson 1,  Priya Mittal 1,  Zhexin Zhu 1,  Baranda S Hansen 5 6,  Katherine A Donovan 3 4,  Moritz Hunkeler 3 4,  Wojciech Rosikiewicz 7,  Zhiping Wu 8,  Meghan G McReynolds 8,  Shourya S Roy Burman 3 4,  Anna M Schmoker 3 4,  Nada Mageed 3,  Scott A Brown 9,  Robert J Mobley 1,  Janet F Partridge 1,  Elizabeth A Stewart 10 11 12,  Shondra M Pruett-Miller 5 6,  Behnam Nabet 13,  Junmin Peng 8 10,  Nathanael S Gray 14,  Eric S Fischer 15 16,  Charles W M Roberts 17 18
Affiliations

Affiliations

  • 1 Division of Molecular Oncology, 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 Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 4 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
  • 5 Department of Cell and Molecular Biology, St Jude Children's Research Hospital, Memphis, TN, USA.
  • 6 The Center for Advanced Genome Engineering, St Jude Children's Research Hospital, Memphis, TN, USA.
  • 7 Center for Applied Bioinformatics, St Jude Children's Research Hospital, Memphis, TN, USA.
  • 8 Department of Structural Biology, St Jude Children's Research Hospital, Memphis, TN, USA.
  • 9 Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA.
  • 10 Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, TN, USA.
  • 11 Department of Oncology, St Jude Children's Research Hospital, Memphis, TN, USA.
  • 12 Cancer Center, St Jude Children's Research Hospital, Memphis, TN, USA.
  • 13 Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
  • 14 Department of Chemical and Systems Biology, ChEM-H, Stanford Cancer Institute, Stanford Medicine, Stanford, CA, USA.
  • 15 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA. eric_fischer@dfci.harvard.edu.
  • 16 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA. eric_fischer@dfci.harvard.edu.
  • 17 Division of Molecular Oncology, Department of Oncology, St Jude Children's Research Hospital, Memphis, TN, USA. charles.roberts@stjude.org.
  • 18 Cancer Center, St Jude Children's Research Hospital, Memphis, TN, USA. charles.roberts@stjude.org.
  • # Contributed equally.
PMID: 38538798 DOI: 10.1038/s41586-024-07250-1
Abstract

Whereas oncogenes can potentially be inhibited with small molecules, the loss of tumour suppressors is more common and is problematic because the tumour-suppressor proteins are no longer present to be targeted. Notable examples include SMARCB1-mutant cancers, which are highly lethal malignancies driven by the inactivation of a subunit of SWI/SNF (also known as BAF) chromatin-remodelling complexes. Here, to generate mechanistic insights into the consequences of SMARCB1 mutation and to identify vulnerabilities, we contributed 14 SMARCB1-mutant cell lines to a near genome-wide CRISPR screen as part of the Cancer Dependency Map Project1-3. We report that the little-studied gene DDB1-CUL4-associated factor 5 (DCAF5) is required for the survival of SMARCB1-mutant cancers. We show that DCAF5 has a quality-control function for SWI/SNF complexes and promotes the degradation of incompletely assembled SWI/SNF complexes in the absence of SMARCB1. After depletion of DCAF5, SMARCB1-deficient SWI/SNF complexes reaccumulate, bind to target loci and restore SWI/SNF-mediated gene expression to levels that are sufficient to reverse the Cancer state, including in vivo. Consequently, Cancer results not from the loss of SMARCB1 function per se, but rather from DCAF5-mediated degradation of SWI/SNF complexes. These data indicate that therapeutic targeting of ubiquitin-mediated quality-control factors may effectively reverse the malignant state of some cancers driven by disruption of tumour suppressor complexes.

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