Disruption of ARID1B recruitment to the nuclear pore complex as a new anticancer therapeutic strategy [ATAC-seq]
Triple-negative breast cancer (TNBC), a highly aggressive subtype, currently lacks potent targeted therapies. ARID1B, a key SWI/SNF chromatin remodeling complex subunit, is linked to high-grade malignancies and poorer prognosis, making it a potential biomarker and therapeutic target. However, its function and regulation remain unclear. Here, we found that uncontrolled accumulation of ARID1B and its nuclear import promoted oncogenesis and drug resistance. ARID1B negatively regulates ARID1A, impairing SWI/SNF-mediated tumor suppression and enhancing tumor survival. Using protein complex purification and mass spectrometry, we identified KPNA2-KPNB1-RANBP2 as a critical protein cascade that facilitates ARID1B nuclear import. Replacing R1518, H1519, and D1522 residues on ARID1B with T1518, G1519, and G1522 attenuated the ARID1B-KPNA2 interaction, preventing recruitment of ARID1B to the nuclear pore complex. Pharmacological inhibition of KPNB1 suppressed ARID1B translocation, thereby limiting its nuclear levels. Our RNA-seq and ATAC-seq analyses indicated that KPNB1 inhibition also mimicked the effects of the SWI/SNF inhibitor on chromatin accessibility and gene expression, likely due to the reduced nuclear levels of ARID1B. In TNBC mouse models, ARID1B knockout significantly reduced tumor growth and enhanced PARP inhibitor efficacy. Collectively, our findings reveal that disrupting ARID1B nuclear translocation could be a new therapeutic strategy for TNBC. Overall design: 1. To investigate the role of KPNB1 in breast cancer, we examined the effect of KPNB1 inhibition using importazole (IPZ) on chromatin accessibility and gene expression in MDA-MB-468 cellls. 2. To investigate whether KPNA2-KPNB1-RANBP2-mediated ARID1B nuclear translocation affects chromatin accessibility and gene expression through the SWI/SNF complex, we conducted RNA-seq and ATAC-seq analysis in MDA-MB-468 cells treated with BRM014 (BRMi). BRMi is a commonly used small-molecule inhibitor that selectively targets the BRG1/BRM ATPase activity of the SWI/SNF complex.