Figure 9.

SIRT1 is important for PGE₂-mediated induction of aromatase expression. Obese women express lower levels of SIRT1 and higher levels of acetyl–HIF-1α, HIF-1α, and aromatase in breast tissue. PGE₂ acted via the EP₂ and EP₄ receptors to induce ATF3, a repressive transcription factor, which bound to a CRE site within the SIRT1 promoter, resulting in reduced SIRT1 levels. The reduction in SIRT1, a deacetylase, leads to elevated levels of acetyl–HIF-1α and HIF-1α and enhanced aromatase transcription. PCAF acetylates HIF-1α and enhances its interaction with p300, a coactivator of CREB, leading to enhanced aromatase transcription. Collectively, these findings suggest the importance of SIRT1-mediated post-translational modification of HIF-1α as a determinant of the elevated levels of aromatase in the breast tissue of obese women.