Acetylation of Androgen Receptor Enhances Coactivator Binding and Promotes Prostate Cancer Cell Growth

Maofu Fu, Mahadev Rao, Chenguang Wang, Toshiyuki Sakamaki, Jian Wang, Dolores Di Vizio, Xueping Zhang, Chris Albanese, Steven Balk, Chawnshang Chang, Saijun Fan, Eliot Rosen, Jorma J. Palvimo, Olli A. Jänne, Selen Muratoglu, Maria Laura Avantaggiati, Richard G. Pestell

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202 Citations (Scopus)

Abstract

Modification by acetylation occurs at E-amino lysine residues of histones and transcription factors. Unlike phosphorylation, a direct link between transcription factor acetylation and cellular growth or apoptosis has not been established. We show that the nuclear androgen receptor (AR), a DNA-binding transcriptional regulator, is acetylated in vivo. The acetylation of the AR is induced by ligand dihydrotestosterone and by histone deacetylase (HDAC) inhibitors in living cells. Direct AR acetylation augmented p300 binding in vitro. Constructs mimicking neutral polar substitution acetylation (AR K630Q, ARK630T) enhanced p300 binding and reduced N-CoR/HDAC/Smad3 corepressor binding, whereas charged residue substitution (ARK630R) reduced p300 binding and enhanced corepressor binding. The AR acetylation mimics promoted cell survival and growth of prostate cancer cells in soft agar and in nude mice and augmented transcription of a subset of growth control target gene promoters. Thus, transcription factor acetylation regulates coactivator/corepressor complex binding, altering expression of specific growth control genes to promote aberrant cellular growth in vivo.

Original languageEnglish
Pages (from-to)8563-8575
Number of pages13
JournalMolecular and Cellular Biology
Volume23
Issue number23
DOIs
Publication statusPublished - 12-2003

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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    Fu, M., Rao, M., Wang, C., Sakamaki, T., Wang, J., Di Vizio, D., Zhang, X., Albanese, C., Balk, S., Chang, C., Fan, S., Rosen, E., Palvimo, J. J., Jänne, O. A., Muratoglu, S., Avantaggiati, M. L., & Pestell, R. G. (2003). Acetylation of Androgen Receptor Enhances Coactivator Binding and Promotes Prostate Cancer Cell Growth. Molecular and Cellular Biology, 23(23), 8563-8575. https://doi.org/10.1128/MCB.23.23.8563-8575.2003