MassIVE MSV000099353

Partial Public PXD069047

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

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Description

Transcriptional dysregulation is a common driver of disease, and damaging mutations in genes that encode members of SWI/SNF chromatin remodeling complexes are found in over 20% of all cancers. Pediatric rhabdoid tumors (RT) constitute an exceptional model with which to study SWI/SNF function, as these aggressive cancers are caused by bi-allelic inactivation of the SWI/SNF subunit SMARCB1 but otherwise contain a diploid and mutationally quiet genome. Here, leveraging robust genome-wide CRISPR screening in hundreds of cancer cell lines, we identify the chromatin reader protein PHIP as a specific vulnerability in RT cells. This finding extends to other cancers with mutations that substantially impair SWI/SNF function, and we demonstrate that dependency upon PHIP is specifically caused by these mutations. PHIP has been shown to recruit E3 ligases to ubiquitinate chromatin-bound targets during replication. Our data reveal a distinct role for PHIP as an activator of transcription by ubiquitinating and degrading members of the repressive NuRD complex. We show that PHIP degrades NuRD member CHD4 at promoters, thus maintaining histone acetylation and gene expression. We demonstrate that this function of PHIP is stimulated by mutations or small molecules that substantially impair SWI/SNF complexes, and this selective dependency extends to patient-derived xenograft models of rhabdoid tumors. Collectively, these findings establish a mechanistic basis of the interplay between these chromatin regulatory complexes and identify PHIP as a specific and targetable vulnerability in select families of SWI/SNF mutant cancers. [doi:10.25345/C5JQ0T76P] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: PHIP ; NuRD ; SWI/SNF ; Cancer ; DatasetType:Proteomics

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Principal Investigators:
(in alphabetical order) 		Charles W. M. Roberts, St. Jude, USA
Submitting User: HMalone
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