HDAC1 Silencing in Ovarian Cancer Enhances the Chemotherapy Response

Abstract

Background/Aims: Cisplatin-based treatment is first-line chemotherapy for several cancers including ovarian cancer. The development of cisplatin resistance results in treatment failure, but the underlying mechanisms are not fully understood. Histone deacetylases (HDACs) are a large family of enzymes that deacetylate lysine residues on histones and non-histone proteins. High expression of HDAC1 is associated with poor outcomes in ovarian cancer. Furthermore, resistance to chemotherapeutic agents is associated with HDAC1 overexpression in ovarian cancer cells. The goals of this study were to determine whether targeting HDAC1 can sensitize ovarian cancer cells to cisplatin and to explore the underlying mechanisms. Methods: Small interfering RNA (siRNA)-targeting HDAC1 was designed to silence HDAC1 in the cisplatin-resistant ovarian cancer cell line A2780^CDDP and its cisplatin-sensitive cell line A2780. The effects of targeting HDAC1 on cell viability assay, colony formation, and apoptosis were detected. c-Myc re-expression or miR-34a inhibitors were used to examine the relationship among HDAC1, c-Myc, and miR-34a expression, which was assessed by western blot analysis and quantitative reverse transcription PCR. We established stable transfectants of A2780^CDDP/HDAC1 short hairpin RNA (shRNA) and A2780/HDAC1 shRNA. The therapeutic effectiveness of cisplatin in murine xenograft models was assessed following shRNA-mediated HDAC1 silencing in A2780^CDDP and A2780 cells. The mechanism of cell death was studied in tumor sections obtained from different mouse tumors. Results: In cisplatin-resistant A2780^CDDP cells, HDAC1 knockdown by siRNA suppressed cell proliferation, and increased apoptosis and chemosensitivity by downregulating c-Myc and upregulating miR-34a. In cisplatin-sensitive A2780 cells, HDAC1 knockdown did not affect cell proliferation and apoptosis. Cisplatin treatment activated HDAC1 and c-Myc and inactivated miR-34a. Inhibition of HDAC1 with siRNA reduced c-Myc expression, increased miR-34a expression, and sensitized A2780 cells to cisplatin-induced apoptosis. c-Myc re-expression or miR-34a targeting by miR-34a inhibitors protected cells from apoptosis or reversed cisplatin resistance following HDAC1 knockdown or/and cisplatin exposure. Finally, in vivo studies showed that targeting HDAC1 inhibited A2780^CDDP-induced xenograft tumor growth but not A2780-induced xenograft tumor growth. Targeting HDAC1 sensitized both A2780- and A2780^CDDP-induced xenograft tumors to cisplatin treatment. Conclusions: Upregulation of HDAC1 is a crucial event in the development of drug resistance to current treatments in ovarian cancer. Thus, targeting HDAC1 by enhancing c-Myc-dependent miR-34a expression might be an effective strategy for increasing the efficacy of cisplatin treatment.

MAGI2‐AS3 suppresses MYC signaling to inhibit cell proliferation and migration in ovarian cancer through targeting miR‐525‐5p/MXD1 axis

“…The significant effects of lncRNAs in OV cells have been explored. For example, lncRNA HDAC1 silencing boosted the chemotherapy response in OV 20 . LncRNA HOTAIR facilitated motility and proliferation in OV via modulating PIK3P3 21 .…”

Resistance to cis- and carboplatin initiated by epigenetic changes in ovarian cancer patients

“…The treatment that influenced the histone structure improved the efficacy of chemotherapy in tumors that had acquired drug resistance due to DNA methylation and gene silencing. Liu et al [94] also performed in vitro and in vivo studies. In cisplatin-resistant ovarian cancer cells, they showed that HDAC1 knockdown suppressed cell proliferation and increased apoptosis.…”

<p>CK19 Promotes Ovarian Cancer Development by Impacting on Wnt/β-Catenin Pathway</p>

“…21 promote the process of malignancy, and is associated with high recurrence, poor overall survival in the patients with ovarian cancer. 22 In the present study, we detected Wnt related genes, including β-catenin, LEF1, TCF7, c-MYC and cyclin D1 in overexpressed CK19 of SKOV3 cells, the results showed that the expression levels of the related genes were all increased. All these data demonstrated that overexpression of CK19 may activate the Wnt/β-catenin signaling pathway in SKOV3 cells.…”