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A noncanonical AR addiction drives enzalutamide resistance in prostate cancer

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  • Yundong He

    (Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science)

  • Ting Wei

    (Division of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine and Science)

  • Zhenqing Ye

    (Division of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine and Science)

  • Jacob J. Orme

    (Division of Medical Oncology, Department of Internal Medicine, Mayo Clinic College of Medicine and Science)

  • Dong Lin

    (Department of Experimental Therapeutics, BC Cancer Research Centre)

  • Haoyue Sheng

    (Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science)

  • Ladan Fazli

    (Department of Experimental Therapeutics, BC Cancer Research Centre)

  • R. Jeffrey Karnes

    (Department of Urology, Mayo Clinic College of Medicine and Science)

  • Rafael Jimenez

    (Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine and Science)

  • Liguo Wang

    (Division of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine and Science)

  • Liewei Wang

    (Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine and Science)

  • Martin E. Gleave

    (University of British Columbia)

  • Yuzhuo Wang

    (Department of Experimental Therapeutics, BC Cancer Research Centre
    University of British Columbia)

  • Lei Shi

    (Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science)

  • Haojie Huang

    (Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science
    Department of Urology, Mayo Clinic College of Medicine and Science
    Mayo Clinic Cancer Center, Mayo Clinic College of Medicine and Science)

Abstract

Resistance to next-generation anti-androgen enzalutamide (ENZ) constitutes a major challenge for the treatment of castration-resistant prostate cancer (CRPC). By performing genome-wide ChIP-seq profiling in ENZ-resistant CRPC cells we identify a set of androgen receptor (AR) binding sites with increased AR binding intensity (ARBS-gained). While ARBS-gained loci lack the canonical androgen response elements (ARE) and pioneer factor FOXA1 binding motifs, they are highly enriched with CpG islands and the binding sites of unmethylated CpG dinucleotide-binding protein CXXC5 and the partner TET2. RNA-seq analysis reveals that both CXXC5 and its regulated genes including ID1 are upregulated in ENZ-resistant cell lines and these results are further confirmed in patient-derived xenografts (PDXs) and patient specimens. Consistent with the finding that ARBS-gained loci are highly enriched with H3K27ac modification, ENZ-resistant PCa cells, organoids, xenografts and PDXs are hyper-sensitive to NEO2734, a dual inhibitor of BET and CBP/p300 proteins. These results not only reveal a noncanonical AR function in acquisition of ENZ resistance, but also posit a treatment strategy to target this vulnerability in ENZ-resistant CRPC.

Suggested Citation

  • Yundong He & Ting Wei & Zhenqing Ye & Jacob J. Orme & Dong Lin & Haoyue Sheng & Ladan Fazli & R. Jeffrey Karnes & Rafael Jimenez & Liguo Wang & Liewei Wang & Martin E. Gleave & Yuzhuo Wang & Lei Shi &, 2021. "A noncanonical AR addiction drives enzalutamide resistance in prostate cancer," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21860-7
    DOI: 10.1038/s41467-021-21860-7
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    Cited by:

    1. Reyaz ur Rasool & Caitlin M. O’Connor & Chandan Kanta Das & Mohammed Alhusayan & Brijesh Kumar Verma & Sehbanul Islam & Ingrid E. Frohner & Qu Deng & Erick Mitchell-Velasquez & Jaya Sangodkar & Aqila , 2023. "Loss of LCMT1 and biased protein phosphatase 2A heterotrimerization drive prostate cancer progression and therapy resistance," Nature Communications, Nature, vol. 14(1), pages 1-24, December.

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