A noncanonical AR addiction drives enzalutamide resistance in prostate cancer

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 () and Haojie Huang ()
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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
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

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-21860-7

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