Procyanidin B3, an inhibitor of histone acetyltransferase, enhances the action of antagonist for prostate cancer cells via inhibition of p300-dependent acetylation of androgen receptor.
Increasing evidence suggests that AR (androgen receptor) acetylation is critical for prostate cancer cell growth. In the present study, we identified Pro-B3 (procyanidin B3) as a specific HAT (histone acetyltransferase) inhibitor. Pro-B3 selectively inhibited the activity of HATs, but not other epigenetic enzymes. Pro-B3 substantially inhibited the p300-mediated AR acetylation, both in vitro and in vivo. Pro-B3 inhibited both p300-dependent and agonist-induced AR transcription. We demonstrate that the p300-mediated AR acetylation is critical for the hormone responsiveness of AR. Interestingly, B3 treatment efficiently enhanced the antagonist activity of flutamide through suppression of p300 HAT activity, demonstrating that relative p300 activity is critical for the antagonist action. Finally, Pro-B3 treatment inhibited acetylation-dependent prostate cell proliferation and expression of cell-cycle control genes, subsequently increasing cell death, indicating the functional importance of AR acetylation for prostate cancer cell growth.
Department of Biochemistry and Molecular Biology, Center for Chronic Metabolic Disease Research, Brain Korea 21 Project for Medical Sciences, Severance Medical Research Institute, Yonsei University College of Medicine, Seoul, South Korea.
Kyung-Chul
KC
Choi
Siyong
S
Park
Beom Jin
BJ
Lim
Ah-Reum
AR
Seong
Ah-Reum
AR
Sung
Yoo-Hyun
YH
Lee
Masaki
M
Shiota
Akira
A
Yokomizo
Seiji
S
Naito
Younghwa
Y
Na
Ho-Geun
HG
Yoon
D000107:Acetylation / Q000187:drug effects; D044946:Biflavonoids / Q000494:pharmacology*; D002392:Catechin / Q000494:pharmacology*; D002453:Cell Cycle / Q000235:genetics; D016923:Cell Death; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D050881:E1A-Associated p300 Protein / Q000378:metabolism*; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors*; D006801:Humans; D008297:Male; D044945:Proanthocyanidins / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology*; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects
D044946:Biflavonoids; D044945:Proanthocyanidins; D011944:Receptors, Androgen; C479581:procyanidin B3; D002392:Catechin; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; D051548:Histone Acetyltransferases