ACY1-mediated deacetylation of GSTP1 at lysine 30 suppresses cisplatin resistance in epithelial ovarian cancer

Abstract

Abstract Resistance to platinum-based chemotherapy is the major limitation to the improvement of epithelial ovarian cancer (EOC) prognosis. Aminoacylase-1 (ACY1) hydrolyzes acylated l-amino acids and N-acetylated proteins; however, the roles of ACY1 in EOC and platinum resistance remain unknown. Accordingly, this study explored the biological functions and clinical significance of ACY1 in the resistance of EOC to cisplatin therapy. We found that lower levels of ACY1 were associated with worse prognosis and platinum-based chemoresistance in EOC. Moreover, ACY1 significantly sensitized EOC cells to cisplatin in vitro and in vivo. Mechanistically, ACY1 deacetylated glutathione S-transferase P1 (GSTP1) at lysine 30, which triggered its degradation and thereby reduced GSTP1 stability. Thus, ACY1 attenuated the intracellular reactive oxygen species (ROS) elimination and DNA damage repair. Finally, histone deacetylase 4 (HDAC4) downregulated ACY1 transcription by suppressing histone H3 lysine 27 acetylation on the ACY1 promoter, and inhibiting HDAC4 reversed cisplatin resistance in EOC cells. Collectively, these results revealed an HDAC4–ACY1–GSTP1 axis as vital signaling for cisplatin resistance in EOC. This suggested that ACY1 might be a novel mediator in EOC chemoresistance and HDAC4 inhibitors could be used to overcome platinum resistance in patients with low expression of ACY1.