Inhibition of SIRT1 deacetylase suppresses estrogen receptor signaling

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