期刊
NATURE COMMUNICATIONS
卷 12, 期 1, 页码 -出版社
NATURE RESEARCH
DOI: 10.1038/s41467-021-21860-7
关键词
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资金
- National Institutes of Health [CA134514, CA130908, CA193239, CA203849]
- Mayo Clinic Foundation
- Canadian Institutes of Health Research [141635, 144159, 153081]
- Terry Fox Research Institute program project [1062]
- Mayo Edward C. Kendall Fellowship
Resistance to next-generation anti-androgen enzalutamide in castration-resistant prostate cancer (CRPC) is a major challenge. Through genome-wide ChIP-seq profiling, it was found that AR-dependent transcription of noncanonical targets drives an ENZ-resistant mechanism, making resistant cells susceptible to dual inhibition of BET and CBP/p300 signaling.
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. Resistance to second generation anti-androgen therapies such as enzalutamide (ENZ) can emerge in prostate cancer patients. Here, the authors identify an ENZ-resistant mechanism driven by AR-dependent transcription of noncanonical targets that make resistant cells susceptible to dual inhibition of BET and CBP/p300 signaling.
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