Targeting estrogen receptor beta (ERβ) for treatment of ovarian cancer: importance of KDM6B and SIRT1 for ERβ expression and functionality

Estrogen receptor (ER) beta has growth inhibitory and chemo drug potentiating effect on ovarian cancer cells. We studied the dependence of ER beta function on the presence of KDM6B and SIRT1 in human ovarian cancer cells in vitro. Activation of ER beta with the subtype-selective agonist KB9520 resulted in significant inhibition of human ovarian cancer cell growth. KB9520-activated ER beta had an additive effect on growth inhibition in combination with cisplatin and paclitaxel, respectively. Loss of KDM6B expression had a negative effect on ER beta function as a ligand-dependent inhibitor of ovarian cancer cell growth. In contrast, loss or inhibition of SIRT1 deacetylase activity restored ligandactivated ER beta functionality. Presented data suggest that selective targeting of ER beta with an agonist potentiate chemotherapy efficacy for the treatment of ovarian cancer and that downregulation or inhibition of SIRT1 may further enhance its therapeutic effect.