Dysregulated BARD1 Contributes to Paclitaxel Resistance in Ovarian Cancer via Up-regulating CYP2C8
Ovarian cancer remains one of the most lethal gynaecological malignancies, with paclitaxel resistance being a major therapeutic challenge that limits treatment efficacy and patient survival. We found that although the BARD1 level was not significantly altered in patients with ovarian cancer (OC), patients with higher BARD1 levels had increased survival time, suggesting that the down-regulation of BARD1 may be related to the paclitaxel sensitivity. Through examining the expression of BARD1 in tumour samples from paclitaxel responders and non-responders, we observed that the BARD1 level was significantly reduced in non-responders. CYP2C8 was up-regulated in non-responders. Also, the BARD1 level was negatively correlated with the level of CYP2C8. BARD1 over-expression in OC cells could repress the CYP2C8 expression, while knockdown of BARD1 could up-regulate CYP2C8 expression, which could be rescued by H2A-Ub. Results from gain and loss of functional experiments indicated that BARD1 functions as a tumour suppressor during paclitaxel treatment, and BARD1 down-regulation increased the IC50 of paclitaxel from 2.46 nM to 5.33 nM in SK-OV-3 cells and from 3.11 nM to 7.51 nM in CaoV-3 cells. We are the first to demonstrate that the down-regulation of BARD1 contributes to paclitaxel resistance via up-regulating CYP2C8 in patients with OC, which provides a potent target for clinical OC treatment.
