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Molecular and Cellular Biology, December 2003, p. 8563-8575, Vol. 23, No. 23
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.23.8563-8575.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

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

Maofu Fu,1 Mahadev Rao,1 Chenguang Wang,1 Toshiyuki Sakamaki,1 Jian Wang,1 Dolores Di Vizio,1 Xueping Zhang,1 Chris Albanese,1 Steven Balk,2 Chawnshang Chang,3 Saijun Fan,1 Eliot Rosen,1 Jorma J. Palvimo,4 Olli A. Jänne,4 Selen Muratoglu,5 Maria Laura Avantaggiati,5 and Richard G. Pestell1*

Department of Oncology, Lombardi Cancer Center, Georgetown University, Washington, D.C. 20057,1 Hematology-Oncology Division, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215,2 George Whipple Laboratory for Cancer Research, Departments of Urology, Pathology, Radiation Oncology, Biochemistry, and Toxicology, and Cancer Center, University of Rochester, Rochester, New York 14642,3 Biomedicum Helsinki, Institute of Biomedicine, and Department of Clinical Chemistry, University of Helsinki, FIN-00014 Helsinki, Finland,4 Department of Pharmacology, George Washington University Medical Center, Washington, D.C. 200375

Received 7 April 2003/ Returned for modification 20 May 2003/ Accepted 27 August 2003

Modification by acetylation occurs at {varepsilon}-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 (ARK630Q, 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.

* Corresponding author. Mailing address: Department of Oncology, Lombardi Comprehensive Cancer Center, Research Building, Room E501, 3970 Reservoir Rd., NW, Box 571468, Georgetown University, Washington, DC 20057. Phone: (202) 687-2100. Fax: (202) 687-4638. E-mail: pestell{at}georgetown.edu.

Molecular and Cellular Biology, December 2003, p. 8563-8575, Vol. 23, No. 23
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.23.8563-8575.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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