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HDAC1 Silencing in Ovarian Cancer Enhances the Chemotherapy Response.
Cell Physiol Biochem. 2018; 48(4):1505-1518.CP

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 A2780CDDP 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 A2780CDDP/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 A2780CDDP and A2780 cells. The mechanism of cell death was studied in tumor sections obtained from different mouse tumors.

RESULTS

In cisplatin-resistant A2780CDDP 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 A2780CDDP-induced xenograft tumor growth but not A2780-induced xenograft tumor growth. Targeting HDAC1 sensitized both A2780- and A2780CDDP-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.

Authors+Show Affiliations

Department of Nuclear Medicine, The Affiliated Hospital of Qingdao University, Qingdao, China.Department of Thyroid Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China.Department of Thyroid Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China.Department of Gynaecology, The Affiliated Hospital of Qingdao University, Qingdao, China.Department of Gynaecology, The Affiliated Hospital of Qingdao University, Qingdao, China.Institute of Pathology and Southwest Cancer Center, Third Military Medical University, Chongqing, China.Department of Radiotherapy, The Affiliated Hospital of Qingdao University, Qingdao, China.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30071534

Citation

Liu, Xinfeng, et al. "HDAC1 Silencing in Ovarian Cancer Enhances the Chemotherapy Response." Cellular Physiology and Biochemistry : International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology, vol. 48, no. 4, 2018, pp. 1505-1518.
Liu X, Yu Y, Zhang J, et al. HDAC1 Silencing in Ovarian Cancer Enhances the Chemotherapy Response. Cell Physiol Biochem. 2018;48(4):1505-1518.
Liu, X., Yu, Y., Zhang, J., Lu, C., Wang, L., Liu, P., & Song, H. (2018). HDAC1 Silencing in Ovarian Cancer Enhances the Chemotherapy Response. Cellular Physiology and Biochemistry : International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology, 48(4), 1505-1518. https://doi.org/10.1159/000492260
Liu X, et al. HDAC1 Silencing in Ovarian Cancer Enhances the Chemotherapy Response. Cell Physiol Biochem. 2018;48(4):1505-1518. PubMed PMID: 30071534.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - HDAC1 Silencing in Ovarian Cancer Enhances the Chemotherapy Response. AU - Liu,Xinfeng, AU - Yu,Ying, AU - Zhang,Jinna, AU - Lu,Caixia, AU - Wang,Liming, AU - Liu,Ping, AU - Song,Hao, Y1 - 2018/08/02/ PY - 2018/01/25/received PY - 2018/07/20/accepted PY - 2018/8/3/pubmed PY - 2018/9/15/medline PY - 2018/8/3/entrez KW - C-Myc KW - Chemoresistance KW - HDAC1 KW - MiR-34a KW - Ovarian cancer SP - 1505 EP - 1518 JF - Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology JO - Cell. Physiol. Biochem. VL - 48 IS - 4 N2 - 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 A2780CDDP 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 A2780CDDP/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 A2780CDDP and A2780 cells. The mechanism of cell death was studied in tumor sections obtained from different mouse tumors. RESULTS: In cisplatin-resistant A2780CDDP 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 A2780CDDP-induced xenograft tumor growth but not A2780-induced xenograft tumor growth. Targeting HDAC1 sensitized both A2780- and A2780CDDP-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. SN - 1421-9778 UR - https://www.unboundmedicine.com/medline/citation/30071534/HDAC1_Silencing_in_Ovarian_Cancer_Enhances_the_Chemotherapy_Response_ L2 - https://www.karger.com?DOI=10.1159/000492260 DB - PRIME DP - Unbound Medicine ER -