BMI1 regulates androgen receptor in prostate cancer independently of the polycomb repressive complex 1

Nat Commun. 2018 Feb 5;9(1):500. doi: 10.1038/s41467-018-02863-3.

Abstract

BMI1, a polycomb group (PcG) protein, plays a critical role in epigenetic regulation of cell differentiation and proliferation, and cancer stem cell self-renewal. BMI1 is upregulated in multiple types of cancer, including prostate cancer. As a key component of polycomb repressive complex 1 (PRC1), BMI1 exerts its oncogenic functions by enhancing the enzymatic activities of RING1B to ubiquitinate histone H2A at lysine 119 and repress gene transcription. Here, we report a PRC1-independent role of BMI1 that is critical for castration-resistant prostate cancer (CRPC) progression. BMI1 binds the androgen receptor (AR) and prevents MDM2-mediated AR protein degradation, resulting in sustained AR signaling in prostate cancer cells. More importantly, we demonstrate that targeting BMI1 effectively inhibits tumor growth of xenografts that have developed resistance to surgical castration and enzalutamide treatment. These results suggest that blocking BMI1 alone or in combination with anti-AR therapy can be more efficient to suppress prostate tumor growth.

Publication types

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

MeSH terms

  • Adenocarcinoma / metabolism*
  • Animals
  • Antineoplastic Agents, Hormonal / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Proliferation / genetics
  • Disease Progression
  • Histones / metabolism
  • Humans
  • Male
  • Mice
  • Mice, SCID
  • Neoplasm Transplantation
  • Orchiectomy
  • Phenylthiohydantoin / analogs & derivatives
  • Phenylthiohydantoin / pharmacology
  • Polycomb Repressive Complex 1 / genetics
  • Polycomb Repressive Complex 1 / metabolism*
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms, Castration-Resistant / metabolism*
  • Proteolysis
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • Receptors, Androgen / metabolism*
  • Signal Transduction
  • Ubiquitination
  • Up-Regulation

Substances

  • Antineoplastic Agents, Hormonal
  • BMI1 protein, human
  • Histones
  • MDV 3100
  • Receptors, Androgen
  • Phenylthiohydantoin
  • MDM2 protein, human
  • Polycomb Repressive Complex 1
  • Proto-Oncogene Proteins c-mdm2
  • RNF2 protein, human