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

Sandi Radko-Juettner, Hong Yue, Jacquelyn A. Myers, Raymond D. Carter, Alexis N. Robertson, Priya Mittal, Zhexin Zhu, Baranda S. Hansen, Katherine A. Donovan, Moritz Hunkeler, Wojciech Rosikiewicz, Zhiping Wu, Meghan G. McReynolds, Shourya S. Roy Burman, Anna M. Schmoker, Nada Mageed, Scott A. Brown, Robert J. Mobley, Janet F. Partridge, Elizabeth A. Stewart, Shondra M. Pruett-Miller, Behnam Nabet, Junmin Peng, Nathanael S. Gray, Eric S. Fischer () and Charles W. M. Roberts ()
Additional contact information
Sandi Radko-Juettner: St Jude Children’s Research Hospital
Hong Yue: Dana-Farber Cancer Institute
Jacquelyn A. Myers: St Jude Children’s Research Hospital
Raymond D. Carter: St Jude Children’s Research Hospital
Alexis N. Robertson: St Jude Children’s Research Hospital
Priya Mittal: St Jude Children’s Research Hospital
Zhexin Zhu: St Jude Children’s Research Hospital
Baranda S. Hansen: St Jude Children’s Research Hospital
Katherine A. Donovan: Dana-Farber Cancer Institute
Moritz Hunkeler: Dana-Farber Cancer Institute
Wojciech Rosikiewicz: St Jude Children’s Research Hospital
Zhiping Wu: St Jude Children’s Research Hospital
Meghan G. McReynolds: St Jude Children’s Research Hospital
Shourya S. Roy Burman: Dana-Farber Cancer Institute
Anna M. Schmoker: Dana-Farber Cancer Institute
Nada Mageed: Dana-Farber Cancer Institute
Scott A. Brown: St Jude Children’s Research Hospital
Robert J. Mobley: St Jude Children’s Research Hospital
Janet F. Partridge: St Jude Children’s Research Hospital
Elizabeth A. Stewart: St Jude Children’s Research Hospital
Shondra M. Pruett-Miller: St Jude Children’s Research Hospital
Behnam Nabet: Fred Hutchinson Cancer Center
Junmin Peng: St Jude Children’s Research Hospital
Nathanael S. Gray: Stanford Cancer Institute, Stanford Medicine
Eric S. Fischer: Dana-Farber Cancer Institute
Charles W. M. Roberts: St Jude Children’s Research Hospital

Nature, 2024, vol. 628, issue 8007, 442-449

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41586-024-07250-1

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