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EZH2 inhibition suppresses endometrial cancer progression via miR-361/Twist axis

Kei Ihira1, Peixin Dong2, Ying Xiong3

  • 1Department of Gynecology, Hokkaido University School of Medicine, Hokkaido University, Sapporo 0608638, Japan.

Oncotarget
|January 16, 2017
PubMed

Insights

EZH2 inhibition reactivates tumor suppressor microRNAs (miRNAs) in endometrial cancer. This approach suppressed cancer cell growth and invasion, offering a promising new therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Enhancer of Zeste Homolog 2 (EZH2) is implicated in cancer progression.
  • MicroRNAs (miRNAs) can function as tumor suppressors.
  • Targeting EZH2 and reactivating tumor suppressor miRNAs are potential anti-cancer strategies.

Purpose of the Study:

  • To investigate the role of EZH2 in regulating specific tumor suppressor miRNAs in endometrial cancer (EC).
  • To evaluate the therapeutic potential of EZH2 inhibition in EC.
  • To explore the miR-361/Twist signaling pathway in EC progression.

Main Methods:

  • Utilized EZH2 inhibitors (GSK343) and siRNA in EC cell lines.
  • Assessed miRNA and gene expression levels (e.g., miR-361, Twist) using quantitative real-time PCR.
  • Evaluated effects on cell proliferation, invasion, and cancer stem cell properties in vitro.
  • Investigated therapeutic efficacy in EC cell xenograft mouse models.
  • Analyzed miRNA expression in primary EC tissues and The Cancer Genome Atlas (TCGA) dataset.

Main Results:

  • EZH2 suppresses tumor suppressors let-7b and miR-361 in EC cells.
  • EZH2, with YY1, epigenetically silences miR-361, leading to Twist upregulation.
  • EZH2 inhibition (GSK343) upregulates miR-361 and downregulates Twist.
  • Combined EZH2 inhibition and hypomethylating agents synergistically reduced EC cell proliferation and invasion.
  • Lower let-7b and miR-361 levels correlate with poorer patient outcomes in EC.
  • EZH2 inhibition decreased tumor growth in vivo.

Conclusions:

  • EZH2 drives EC progression via regulation of the miR-361/Twist axis.
  • EZH2 inhibition demonstrates significant anti-cancer effects in endometrial cancer.
  • Targeting EZH2 represents a promising therapeutic strategy for endometrial cancer treatment.
Keywords:
5-AZA-CdREZH2GSK343endometrial cancermiR-361

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