Inhibition of SIRT1 deacetylase suppresses estrogen receptor signaling
N. E Davidson
Estrogen receptor (ER) 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 ER signaling. Here, we report that human SIRT1, a class III HDAC, regulates ER expression. Inhibition of SIRT1 activity by sirtinol suppresses ER expression through disruption of basal transcriptional complexes at the ER promoter. This effect leads to inhibition of estrogen-responsive gene expression. Our in vitro observations were further extended that SIRT1 knockout reduces ER protein in mouse mammary gland. Finally, ER-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 ER-mediated signaling pathways.