A noncanonical AR addiction drives enzalutamide resistance in prostate cancer

Nat Commun. 2021 Mar 9;12(1):1521. doi: 10.1038/s41467-021-21860-7.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androgen Antagonists / pharmacology
  • Angiotensin Receptor Antagonists
  • Angiotensin-Converting Enzyme Inhibitors / pharmacology
  • Animals
  • Benzamides
  • Binding Sites
  • Cell Proliferation / drug effects
  • DNA-Binding Proteins / metabolism
  • Hepatocyte Nuclear Factor 3-alpha / metabolism
  • Humans
  • Male
  • Mice
  • Mice, SCID
  • Nitriles
  • Organoids
  • Phenylthiohydantoin / analogs & derivatives*
  • Phenylthiohydantoin / pharmacology*
  • Prostatic Neoplasms / drug therapy
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / pathology
  • Receptors, Androgen / metabolism*
  • Signal Transduction / drug effects
  • Transcription Factors / metabolism
  • Up-Regulation
  • Xenograft Model Antitumor Assays


  • Androgen Antagonists
  • Angiotensin Receptor Antagonists
  • Angiotensin-Converting Enzyme Inhibitors
  • Benzamides
  • CXXC5 protein, human
  • DNA-Binding Proteins
  • FOXA1 protein, human
  • Hepatocyte Nuclear Factor 3-alpha
  • Nitriles
  • Receptors, Androgen
  • Transcription Factors
  • Phenylthiohydantoin
  • enzalutamide