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Cancer Biother Radiopharm. 2016 Sep;31(7):246-52. doi: 10.1089/cbr.2016.2034.

Interfering EZH2 Expression Reverses the Cisplatin Resistance in Human Ovarian Cancer by Inhibiting Autophagy.

Author information

1
1 Department of Gynecology, Fujian Provincial Hospital, Fujian Provincial Clinical Medical College, Fujian Medical University , Fuzhou, China .
2
2 Department of Pathology, Fujian Provincial Hospital, Fujian Provincial Clinical Medical College, Fujian Medical University , Fuzhou, China .
3
3 Department of Pharmacy, Fujian Provincial Hospital, Fujian Provincial Clinical Medical College, Fujian Medical University , Fuzhou, China .
4
4 Fujian Provincial Key Laboratory of Cardiovascular Disease, Fujian Provincial Hospital, Fujian Medical University , Fuzhou, China .

Abstract

We aimed to determine the effects of the inhibition of enhancer of zeste homolog 2 (EZH2) gene expression on the cisplatin resistance of the human ovarian cancer cell line, SKOV3/DDP, and to identify the underlying mechanisms. SKOV3/DDP cells were stably transfected with pSUPER-EZH2 (EZH2 RNA interference plasmid) or pcDNA3.1-EZH2 (EZH2 gene overexpression plasmid) using the lipofection method. Real-time fluorescence quantitative reverse transcription polymerase chain reaction and western blotting confirmed that EZH2 expression was downregulated in pSUPER-EZH2-transfected cells. Flow cytometry revealed that EZH2 inhibition did not induce apoptosis, but significantly inhibited autophagy. In addition, it significantly increased the expression of the cellular senescence-signaling proteins p14(ARF), p16(INK4a), p53, pRb, and p21, and significantly decreased the expression of cyclin-dependent kinase (CDK)1, CDK2, and H3K27me3. Cellular senescence was characterized by a significant increase in the G0/G1 ratio and the restoration of sensitivity to cisplatin in the drug-resistant cells. These findings suggest that interfering with EZH2 expression can inhibit SKOV3/DDP cell autophagy and reverse resistance to cisplatin. The underlying mechanisms could be associated with the regulation of the cellular senescence-signaling pathway.

KEYWORDS:

EZH2; autophagy; cisplatin; ovarian cancer

PMID:
27610467
DOI:
10.1089/cbr.2016.2034
[Indexed for MEDLINE]

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