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Advanced Science

Advanced Science

IF: 14.3
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Disruption of ARID1B Recruitment to the Nuclear Pore Complex as a New Anticancer Therapeutic Strategy

Published:16 July 2025 DOI: 10.1002/advs.202415585 PMID: 40671262
Olena Odnokoz, Anupam Banerjee, Xin Cui, Lidan Zeng, Amad Uddin, Christopher Li, Yueming Zhu, Mengyuan Zhang, Xiaodong Lu, Nagendra S. Yarla, Lu Wang, Jindan Yu, Jonathan C. Zhao, Ivet Bahar, Yong Wan

Abstract

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 poor prognosis, making it a potential biomarker and therapeutic target. However, its function and regulation remain unclear. Here, it is found that uncontrolled accumulation of ARID1B and its dysregulated 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, the KPNA2–KPNB1–RANBP2 protein cascade is identified as critical for facilitating ARID1B nuclear import. Replacing R1518, H1519, and D1522 residues on ARID1B with T1518, G1519, and G1522 attenuates the ARID1B–KPNA2/KPNB1 interaction, preventing recruitment of ARID1B to the nuclear pore complex (NPC). Pharmacologically inhibiting KPNB1 suppressed ARID1B translocation, limiting its nuclear levels. In TNBC mouse models, ARID1B knockout (KO) significantly reduces tumor growth and enhances PARP inhibitor efficacy. Collectively, these findings uncover an undocumented mechanism for ARID1B nuclear translocation and reveal that blockade of ARID1B nuclear translocation can be a new therapeutic strategy for TNBC.

Substances (14)

Materials
Procduct Name CAS Molecular Formula Supplier Price
Neratinib 698387-09-6 C30H29ClN6O3 404 suppliers $10.00-$5273.00
Neratinib 698387-09-6 C30H29ClN6O3 404 suppliers $10.00-$5273.00
Neratinib 698387-09-6 C30H29ClN6O3 404 suppliers $10.00-$5273.00
Neratinib 698387-09-6 C30H29ClN6O3 404 suppliers $10.00-$5273.00
Tucatinib 937263-43-9 C26H24N8O2 243 suppliers $9.00-$2500.00
Tucatinib 937263-43-9 C26H24N8O2 243 suppliers $9.00-$2500.00
Tucatinib 937263-43-9 C26H24N8O2 243 suppliers $9.00-$2500.00
Tucatinib 937263-43-9 C26H24N8O2 243 suppliers $9.00-$2500.00
N-(1-phenylethyl)-2-(pyrrolidin-1-yl)quinazolin-4-aMine 662163-81-7 C20H22N4 99 suppliers $10.00-$5372.00
N-(1-phenylethyl)-2-(pyrrolidin-1-yl)quinazolin-4-aMine 662163-81-7 C20H22N4 99 suppliers $10.00-$5372.00

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