PBRM1-deficient PBAF complexes target aberrant genomic loci to activate the NF-κB pathway in clear cell renal cell...

Area of Science:

• Oncology
• Molecular Biology
• Chromatin Biology

Background:

• PBRM1 (Polybromo and RING Finger 1) is a subunit of the PBAF (Polybromo-associated BRG1-associated factor) SWI/SNF chromatin remodeler.
• PBRM1 inactivation is common in kidney cancer, but its functional impact on chromatin remodeling and tumorigenesis is not fully understood.

Purpose of the Study:

• To investigate the consequences of PBRM1 loss on PBAF complex function and chromatin accessibility in VHL-deficient renal tumors.
• To elucidate the role of PBRM1 deficiency in activating pro-tumourigenic pathways, specifically NF-κB.
• To explore potential therapeutic strategies targeting PBRM1-deficient kidney cancer.

Main Methods:

• Analysis of PBRM1-deficient VHL-deficient renal tumors and cell models.
• Chromatin immunoprecipitation sequencing (ChIP-seq) to assess PBAF complex localization and NF-κB (Nuclear Factor kappa-light-chain-enhancer of activated B cells) binding.
• Biochemical assays to characterize PBAF complex composition and SMARCA4 ATPase activity.
• Treatment with proteasome inhibitor bortezomib to evaluate its effect on NF-κB activation and tumor growth.

Main Results:

• PBRM1 deficiency causes PBAF complexes to ectopically localize to new genomic sites, including distal enhancers with NF-κB motifs.
• PBAF complexes in PBRM1-deficient cells exhibit altered composition (loosely tethered BRD7) but maintain SMARCA4-ARID2 association.
• SMARCA4 ATPase activity drives chromatin occupancy of RELA (a subunit of NF-κB) at specific loci, leading to heightened NF-κB pathway activation and downstream gene expression.
• Bortezomib treatment reduces RELA occupancy, suppresses NF-κB signaling, and inhibits the growth of PBRM1-deficient tumors.

Conclusions:

• PBRM1 normally acts as a tumor suppressor by preventing aberrant activation of NF-κB target genes through PBAF chromatin remodeling.
• PBRM1 loss unleashes pro-tumourigenic NF-κB activity by allowing PBAF complexes to access and activate specific enhancer elements.
• Targeting the NF-κB pathway, for instance with bortezomib, represents a promising therapeutic approach for kidney cancers with PBRM1 deficiency.