ZEINAB AMINI FARSANI - Department of Biology, University of Sistan and Baluchestan, Zahedan, Iran. Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Rahmatiyeh, Shahrekord, Iran.
Zahre sajadpoor - Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Rahmatiyeh, Shahrekord, Iran.
Hossein TEIMORI - Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Rahmatiyeh, Shahrekord, Iran.
Hashemi hashemi - National Institute of Genetic Engineering and Biotechnology, Tehran, Iran
mehdi shamsara - National Research Center for Transgenic Mouse, National Institute of Genetic Engineering and Biotechnology,Tehran, Iran
Elham hosseini - IVF center, Mousavi Hospital, Zanjan University of Medical Sciences, Zanjan, Iran.

Objective: Resistance to chemotherapy drugs, including cisplatin, is a major obstacle to effective treatment of ovarian cancer. Recent evidence suggests that lncRNA H19 correlates with drug resistance in different cancers. Valproic acid (VPA) is a histone deacetylase inhibitor that has anti-cancer effects. The objectives of this study were to investigate VPA effects on H19 expression and also the relation of the H19 levels with apoptosis and cisplatin-resistance in ovarian cancer cells.Methods: A2780/CP cells were treated with cisplatin and/or VPA for 48 hours. The cell viability was evaluated using MTT assay and the apoptosis was measured using flow cytometry. The expression of genes and proteins were determined by qRT-PCR and western blotting, respectively. Also, the involvement of H19 in VPA-induced apoptosis and cisplatin-sensitivity, was investigated by H19 inhibition using specific siRNA. Results: Treatment with VPA, not only led to significant increase in apoptosis rate, but also increased the cisplatin-sensitivity of A2780/CP cells. Our results showed that following VPA treatment, the expression of H19 and EZH2 decreased, but the expression of p21 and PTEN increased significantly. Moreover, knockdown of H19 by siRNA induced apoptosis and sensitized the A2780/CP cells to cisplatin-induced cytotoxicity.Conclusion: These data indicated that VPA suppresses H19 expression in ovarian cancer cells, which subsequently leads to apoptosis induction, cell proliferation inhibition and overwhelming to cisplatin-resistance. The implication of H19→EZH2→p21/PTEN pathway by VPA treatment suggests that we could repurpose an old drug, valproic acid, as an effective drug for treatment of ovarian cancer in the future.

Cisplatin; EZH2; H19; Ovarian cancer; Valproic acid