2. Academic Validation
  3. Disruption of ARID1B Recruitment to the Nuclear Pore Complex as a New Anticancer Therapeutic Strategy

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

  • Adv Sci (Weinh). 2025 Jul 16:e15585. doi: 10.1002/advs.202415585.
Olena Odnokoz 1 2,  Anupam Banerjee 3,  Xin Cui 1 2,  Lidan Zeng 1 2,  Amad Uddin 1 2,  Christopher Li 1 2,  Yueming Zhu 1 2,  Mengyuan Zhang 4,  Xiaodong Lu 5,  Nagendra S Yarla 1 2,  Lu Wang 6,  Jindan Yu 5,  Jonathan C Zhao 7,  Ivet Bahar 3 8,  Yong Wan 1 2
Affiliations

Affiliations

  • 1 Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, 30322, USA.
  • 2 Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, 30322, USA.
  • 3 Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, NY, 11794, USA.
  • 4 Department of Biochemistry and Molecular Biology and Institute of Bioinformatics, University of Georgia, Athens, GA, 30602, USA.
  • 5 Department of Urology, Emory University School of Medicine, Atlanta, GA, 30322, USA.
  • 6 Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
  • 7 Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, 30322, USA.
  • 8 Department of Biochemistry and Cell Biology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, 11794, USA.
PMID: 40671262 DOI: 10.1002/advs.202415585
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.

Keywords

ARID1B; KPNA2; KPNB1; RANBP2; carcinogenesis; nuclear translocation.

Figures
Products