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

Background: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.

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