Interfering EZH2 Expression Reverses the Cisplatin Resistance in Human Ovarian Cancer by Inhibiting Autophagy.
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.
1 Department of Gynecology, Fujian Provincial Hospital, Fujian Provincial Clinical Medical College, Fujian Medical University , Fuzhou, China .
Yang
Y
Sun
2 Department of Pathology, Fujian Provincial Hospital, Fujian Provincial Clinical Medical College, Fujian Medical University , Fuzhou, China .
Long
L
Jin
1 Department of Gynecology, Fujian Provincial Hospital, Fujian Provincial Clinical Medical College, Fujian Medical University , Fuzhou, China .
Jia-Hua
JH
Liu
3 Department of Pharmacy, Fujian Provincial Hospital, Fujian Provincial Clinical Medical College, Fujian Medical University , Fuzhou, China .
Yu-Xia
YX
Sui
4 Fujian Provincial Key Laboratory of Cardiovascular Disease, Fujian Provincial Hospital, Fujian Medical University , Fuzhou, China .
Li-Li
LL
Han
4 Fujian Provincial Key Laboratory of Cardiovascular Disease, Fujian Provincial Hospital, Fujian Medical University , Fuzhou, China .
Xiao-Li
XL
Shen
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001343:Autophagy; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D015870:Gene Expression; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D000970:Antineoplastic Agents; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D002945:Cisplatin
EZH2; autophagy; cisplatin; ovarian cancer