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

Area of Science:

• Oncology
• Molecular Biology
• Epigenetics

Background:

• Cisplatin resistance is a major challenge in ovarian cancer treatment.
• Enhancer of zeste homolog 2 (EZH2) is implicated in various cancers and epigenetic regulation.
• The role of EZH2 in cisplatin resistance and its underlying mechanisms in ovarian cancer remain to be fully elucidated.

Purpose of the Study:

• To investigate the impact of EZH2 gene expression inhibition on cisplatin resistance in the SKOV3/DDP human ovarian cancer cell line.
• To identify the molecular mechanisms through which EZH2 affects cisplatin sensitivity.

Main Methods:

• Stable transfection of SKOV3/DDP cells with EZH2 RNA interference or overexpression plasmids.
• Quantitative reverse transcription PCR and Western blotting to assess EZH2 expression levels.
• Flow cytometry to analyze apoptosis, autophagy, cell cycle distribution, and expression of key senescence-related proteins.

Main Results:

• EZH2 expression was successfully downregulated using RNA interference.
• EZH2 inhibition significantly suppressed autophagy and did not induce apoptosis.
• Downregulation of EZH2 led to increased expression of p14(ARF), p16(INK4a), p53, pRb, and p21, and decreased expression of CDK1, CDK2, and H3K27me3.
• Cellular senescence was induced, characterized by an increased G0/G1 phase ratio.
• Restored sensitivity to cisplatin in drug-resistant SKOV3/DDP cells.

Conclusions:

• Interfering with EZH2 expression can inhibit autophagy and reverse cisplatin resistance in SKOV3/DDP ovarian cancer cells.
• The observed effects are potentially mediated through the regulation of the cellular senescence-signaling pathway.
• Targeting EZH2 may represent a novel therapeutic strategy to overcome cisplatin resistance in ovarian cancer.