p300 acetyltransferase regulates androgen receptor degradation and PTEN-deficient prostate tumorigenesis.
Overexpression of the histone acetyltransferase p300 is implicated in the proliferation and progression of prostate cancer, but evidence of a causal role is lacking. In this study, we provide genetic evidence that this generic transcriptional coactivator functions as a positive modifier of prostate tumorigenesis. In a mouse model of PTEN deletion-induced prostate cancer, genetic ablation of p300 attenuated expression of the androgen receptor (AR). This finding was confirmed in human prostate cancer cells in which PTEN expression was abolished by RNA interference-mediated attenuation. These results were consistent with clinical evidence that the expression of p300 and AR correlates positively in human prostate cancer specimens. Mechanistically, PTEN inactivation increased AR phosphorylation at serine 81 (Ser81) to promote p300 binding and acetylation of AR, thereby precluding its polyubiquitination and degradation. In support of these findings, in PTEN-deficient prostate cancer in the mouse, we found that p300 was crucial for AR target gene expression. Taken together, our work identifies p300 as a molecular determinant of AR degradation and highlights p300 as a candidate target to manage prostate cancer, especially in cases marked by PTEN loss.
Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.|Department of Urology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.|Mayo Clinic Cancer Center, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Jian
J
Zhong
Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.|Department of Urology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.|Mayo Clinic Cancer Center, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Liya
L
Ding
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA.
Laura R
LR
Bohrer
Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Yunqian
Y
Pan
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA.
Ping
P
Liu
Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Jun
J
Zhang
Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Thomas J
TJ
Sebo
Department of Urology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
R Jeffrey
RJ
Karnes
Department of Urology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.|Mayo Clinic Cancer Center, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Donald J
DJ
Tindall
Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.|Mayo Clinic Cancer Center, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Jan
J
van Deursen
Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.|Department of Urology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.|Mayo Clinic Cancer Center, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Haojie
H
Huang
D000368:Aged; D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics*; D010766:Phosphorylation; D019048:Prostatic Intraepithelial Neoplasia / Q000201:enzymology* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000473:pathology; D059748:Proteolysis; D011944:Receptors, Androgen / Q000378:metabolism*; D014158:Transcription, Genetic; D054875:Ubiquitination; D050880:p300-CBP Transcription Factors / Q000502:physiology*; D000099224:p300-CBP-Associated Factor
D051059:PTEN Phosphohydrolase; D011944:Receptors, Androgen; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C487757:Pten protein, mouse