Valproic Acid Promotes Apoptosis and Cisplatin Sensitivity Through Downregulation of H19 Noncoding RNA in Ovarian A2780 Cells

Abstract

Cisplatin resistance is one of the main limitations in the treatment of ovarian cancer, which is partly mediated by long noncoding RNAs (lncRNAs). H19 is a lncRNA involving in cisplatin resistance in cancers. Valproic acid (VPA) is a commonly used drug for clinical treatment of seizure disorders. In addition, this drug may display its effects through regulation of noncoding RNAs controlling gene expression. The aim of the present study was the investigation of VPA treatment effect on H19 expression in ovarian cancer cells and also the relation of the H19 levels with apoptosis and cisplatin resistance. Briefly, treatment with VPA not only led to significant increase in apoptosis rate, but also increased the cisplatin sensitivity of A2780/CP cells. We found that following VPA treatment, the expression of H19 and EZH2 decreased, but the expression of p21 and PTEN increased significantly. To investigate the involvement of H19 in VPA-induced apoptosis and cisplatin sensitivity, H19 was inhibited by a specific siRNA. Our results demonstrate that H19 knockdown by siRNA induced apoptosis and sensitized the A2780/CP cells to cisplatin-induced cytotoxicity. These data indicated that VPA negatively regulates the expression of H19 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.

NCALD affects drug resistance and prognosis by acting as a ceRNA of CX3CL1 in ovarian cancer

“…Although platinum‐based chemotherapy has improved patient survival over the past 30 years, most patients with advanced OC experience recurrence and develop a drug‐resistant disease. In these patients, drug resistance is considered to be the leading cause for cancer treatment failure due to a series of contributing factors such as microRNA (miRNA) regulation, 2 protein‐protein interaction, 3 long noncoding RNA regulation, 4 growth factor receptor regulation, 5 and metabolic disturbances 6 . Aberrations in these physiological processes frequently stem from the dysregulation of key genes 7 .…”

Long Noncoding RNA 00473 Is Involved in Preeclampsia by LSD1 Binding-Regulated TFPI2 Transcription in Trophoblast Cells

“… 18 Research of the past decade has implicated a number of lncRNAs in aging, neurological diseases, and cancer, thus providing a new dimension in our understanding of the molecular mechanisms involved in normal physiological processes and disease. The expression of lncRNAs is correlated with such cellular processes as apoptosis, 19 cell proliferation, 20 migration, 21 and stem cell pluripotency. 22 The recent data indicate that lncRNAs may play a role in the pathogenesis of PE by regulating trophoblast invasion and apoptosis.…”

Identification of Potential Markers for Differentiating Epithelial Ovarian Cancer from Ovarian Low Malignant Potential Tumors through Integrated Bioinformatics Analysis

“…Moreover, the top 15 chemicals screened by Cytoscape were found to be related with all 5 genes. Among them, valproic acid [65,66], Calcitriol [67,68], cobaltous chloride [69], Copper Sulfate [70,71], Genistein [72], 7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide [73], Methotrexate [74], Mustard Gas [75] and Cyclosporine [76] all have been showed to have antitumor activity against EOC in vitro or vivo, whereas bisphenol A [77,78], cadmium [79,80], A atoxin B1 [81] and Estradiol [82,83] all have cancerpromoting activity in EOC. However, Lucanthone and Latex have not been studied in EOC till now despite they showed anti-cancer effects in other cancers [84,85].…”