OncoTargets and Therapy (Nov 2019)

EZH2 Contributes To Cisplatin Resistance In Breast Cancer By Epigenetically Suppressing miR-381 Expression

  • Dou D,
  • Ge X,
  • Wang X,
  • Xu X,
  • Zhang Z,
  • Seng J,
  • Cao Z,
  • Gu Y,
  • Han M

Journal volume & issue
Vol. Volume 12
pp. 9627 – 9637

Abstract

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Dongwei Dou,* Xin Ge,* Xinxing Wang, Xiaodong Xu, Zhe Zhang, Jingjing Seng, Zhang Cao, Yuanting Gu, Mingli Han Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 475000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Mingli HanDepartment of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, 1 Jianshe East Road, Zhengzhou 450000, Henan Province, People’s Republic of ChinaTel +86-371-66273586Email [email protected]: Emerging evidence reveals the vital role of enhancer of zeste homolog 2 (EZH2) in cancer chemoresistance. However, its function and molecular mechanisms in breast cancer chemoresistance remain largely unknown.Methods: Gene expression was evaluated using quantitative real-time PCR (qRT-PCR) and Western blot analysis. The functional roles of EZH2 and miR-381 in breast cancer were explored using cell MTT assay and flow cytometry analysis. The effect of EZH2 on miR-381 expression in transcriptional level was determined using Chromatin immunoprecipitation (ChIP) assay and Luciferase reporter assay.Results: In this study, we found that EZH2 was up-regulated in CDDP-resistant breast cancer tissues and cell lines. Breast cancer patients with high EZH2 expression had a poor prognosis. EZH2 silencing improved the sensitivity of MCF-7/CDDP and MDA-MB-231/CDDP cells towards CDDP. Moreover, EZH2 could epigenetically silence miR-381. miR-381 overexpression could overcome CDDP resistance in CDDP-resistant breast cancer cells. miR-381 knockdown weakened the inductive effect of EZH2 silencing on CDDP sensitivity of MCF-7/CDDP and MDA-MB-231/CDDP cells. Furthermore, EZH2 knockdown facilitated CDDP sensitivity of CDDP-resistant breast cancer cells in vivo.Conclusions: Collectively, EZH2 depletion overcame CDDP resistance of breast cancer through epigenetically silencing miR-381, providing a novel therapeutic target for breast cancer chemoresistance.Keywords: breast cancer, CDDP, enhancer of zeste homolog 2, miR-381

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