Abstract B006: PBRM1-deficient PBAF complexes target de novo genomic loci to activate NF-κB pathway in kidney cancer


 Polybromo-1 (PBRM1) is the second most commonly mutated gene in kidney cancer after VHL, occurring at a frequency of 30-40%. PBRM1 loss represents a tumor-initiating event and the combined loss of VHL and PBRM1 is necessary and sufficient for renal malignancy. Functionally, PBRM1 is the defining subunit of the polybromo BRG1-associated factor (PBAF) subclass of SWItch/Sucrose Non-Fermentable (SWI/SNF) remodeling complex which regulates chromatin accessibility by sliding, depositing or evicting nucleosomes. Determining context-specific chromatin remodeling by PBRM1 is paramount to understanding how PBRM1 deficiency drives kidney tumorigenesis. We compared the association of SWI/SNF subunits in the presence or absence of PBRM1 and found that PBRM1 loss resulted in a PBAF complex that has undergone alterations in its configuration and targeting specificity: First, the histone binding lobe disengages from the central ATPase subunit. Second, the PBRM1-deficient complexes, despite retaining the DNA binding lobe, occupy aberrant sites, redistributing from promoter proxy regions to distal enhancer regions. The aberrant sites mapped to regions enriched for NF-κB motifs. Indeed, PBRM1-deficient tumors show enhanced NF-κB activity across isogenic tumor models, genetically modified mouse models and clinical samples. We believe that the PBRM1-deficient PBAF complexes enhance the recruitment of nuclear factor RELA, a subunit of the NF-κB complex - this recruitment requires the ATPase function of the SWI/SNF complexes since BRG1/BRM ATPase inhibitor dampens the expression of NF-κB target genes and RELA chromatin occupancy. Proteasome inhibitor bortezomib reverses NF-κB activity by reducing RELA binding at regions bound by PBRM1-deficient PBAF and delays PBRM1-deficient tumor growth. In conclusion, the PBRM1 tumor suppressor safeguards the chromatin by repressing aberrant liberation of pro-tumorigenic NF-κB target genes by residual PBRM1-deficient PBAF complexes. Inhibition of NF-κB activity by bortezomib could be a therapeutic strategy for PBRM1-deficient kidney cancer.
 Citation Format: Xiaosai Yao, Jing Han Hong, Amrita Nargund, Bin Tean Teh. PBRM1-deficient PBAF complexes target de novo genomic loci to activate NF-κB pathway in kidney cancer. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr B006.