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Oncogene. 2018 Mar;37(10):1326-1339. doi: 10.1038/s41388-017-0047-5. Epub 2017 Dec 18.

DBC1 promotes castration-resistant prostate cancer by positively regulating DNA binding and stability of AR-V7.

Author information

1
Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea.
2
Department of Biomedical Sciences, Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea.
3
Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
4
Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
5
Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea. jeongkim@skku.edu.
6
Department of Biomedical Sciences, Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea. jeongkim@skku.edu.

Abstract

Constitutively active AR-V7, one of the major androgen receptor (AR) splice variants lacking the ligand-binding domain, plays a key role in the development of castration-resistant prostate cancer (CRPC) and anti-androgen resistance. However, our understanding of the regulatory mechanisms of AR-V7-driven transcription is limited. Here we report DBC1 as a key regulator of AR-V7 transcriptional activity and stability in CRPC cells. DBC1 functions as a coactivator for AR-V7 and is required for the expression of AR-V7 target genes including CDH2, a mesenchymal marker linked to CRPC progression. DBC1 is required for recruitment of AR-V7 to its target enhancers and for long-range chromatin looping between the CDH2 enhancer and promoter. Mechanistically, DBC1 enhances DNA-binding activity of AR-V7 by direct interaction and inhibits CHIP E3 ligase-mediated ubiquitination and degradation of AR-V7 by competing with CHIP for AR-V7 binding, thereby stabilizing and activating AR-V7. Importantly, DBC1 depletion suppresses the tumorigenic and metastatic properties of CRPC cells. Our results firmly establish DBC1 as a critical AR-V7 coactivator that plays a key role in the regulation of DNA binding and stability of AR-V7 and has an important physiological role in CRPC progression.

PMID:
29249800
DOI:
10.1038/s41388-017-0047-5

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