Androgen receptor degradation by the E3 ligase CHIP modulates mitotic arrest in prostate cancer cells

Oncogene. 2014 Jan 2;33(1):26-33. doi: 10.1038/onc.2012.561. Epub 2012 Dec 17.


The androgen receptor (AR) has a vital role in the onset and progression of prostate cancer by promoting G1-S progression, possibly by functioning as a licensing factor for DNA replication. We here report that low dose 2-methoxyestradiol (2-ME), an endogenous estrogen metabolite, induces mitotic arrest in prostate cancer cells involving activation of the E3 ligase CHIP (C-terminus of Hsp70-interacting protein) and degradation of the AR. Depletion of the AR by small interfering RNA (siRNA) eliminates 2-ME-induced arrest and introducing AR into PC3-M cells confers 2-ME-induced mitotic arrest. Knockdown of CHIP or MDM2 (mouse homolog of double minute 2 protein) individually or in combination reduced AR degradation and abrogated M phase arrest induced by 2-ME. Our data link AR degradation via ubiquitination to mitotic arrest. Targeting the AR by activating E3 ligases such as CHIP represents a novel strategy for the treatment of prostate cancer.

Publication types

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

MeSH terms

  • 2-Methoxyestradiol
  • Angiogenesis Inhibitors / pharmacology
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm
  • Estradiol / analogs & derivatives
  • Estradiol / pharmacology
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Knockdown Techniques
  • Humans
  • M Phase Cell Cycle Checkpoints
  • Male
  • Prostatic Neoplasms
  • Proteasome Endopeptidase Complex / metabolism
  • Proteolysis*
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • RNA, Small Interfering / genetics
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism*
  • Tubulin Modulators / pharmacology
  • Tumor Suppressor Protein p53 / metabolism
  • Ubiquitin-Protein Ligases / physiology*


  • AR protein, human
  • Angiogenesis Inhibitors
  • RNA, Small Interfering
  • Receptors, Androgen
  • TP53 protein, human
  • Tubulin Modulators
  • Tumor Suppressor Protein p53
  • Estradiol
  • 2-Methoxyestradiol
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2
  • STUB1 protein, human
  • Ubiquitin-Protein Ligases
  • Proteasome Endopeptidase Complex