Inhibition of SIRT1 deacetylase suppresses estrogen receptor signaling.
Estrogen receptor alpha (ERalpha) mediates estrogen-dependent gene transcription, which plays a critical role in mammary gland development, reproduction and homeostasis. Histone acetyltransferases and class I and class II histone deacetylases (HDACs) cause posttranscriptional modification of histone proteins that participate in ERalpha signaling. Here, we report that human SIRT1, a class III HDAC, regulates ERalpha expression. Inhibition of SIRT1 activity by sirtinol suppresses ERalpha expression through disruption of basal transcriptional complexes at the ERalpha promoter. This effect leads to inhibition of estrogen-responsive gene expression. Our in vitro observations were further extended that SIRT1 knockout reduces ERalpha protein in mouse mammary gland. Finally, ERalpha-mediated estrogen response genes are also decreased in mouse embryonic fibroblasts derived from SIRT1-knockout mice. These results suggest that inhibition of SIRT1 deacetylase activity by either pharmacological inhibitors or genetic depletion impairs ERalpha-mediated signaling pathways.
Yao
Yuan
Y
Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Li
Hongzhe
H
Gu
Yansong
Y
Davidson
Nancy E
NE
Zhou
Qun
Q
D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001943:Breast Neoplasms / Q000473:pathology; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured / Q000166:cytology / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009284:Naphthols / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D009536:Niacinamide / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013047:Specific Pathogen-Free Organisms; D014158:Transcription, Genetic / Q000187:drug effects
D001549:Benzamides; D047628:Estrogen Receptor alpha; D009284:Naphthols; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; C439060:sirtinol; D009536:Niacinamide; D004958:Estradiol; C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1