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Silencing of Kruppel-like factor 2 by the histone methyltransferase EZH2 in human cancer

H Taniguchi1, F V Jacinto, A Villanueva

  • 1Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.

Oncogene
|September 6, 2011
PubMed

Insights

Epigenetic silencing of KLF2 by EZH2 suppresses its tumor suppressor function in cancer. Restoring KLF2 inhibits tumor growth and improves survival in preclinical models and human patients.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Epigenetics

Background:

  • Kruppel-like factor (KLF) proteins are transcriptional regulators with tumor suppressor roles.
  • KLF2 exhibits diminished expression in malignancies, possessing growth-inhibitory, pro-apoptotic, and anti-angiogenic functions.

Purpose of the Study:

  • To investigate the epigenetic mechanisms underlying KLF2 silencing in cancer.
  • To elucidate the role of Enhancer of Zeste Homolog 2 (EZH2) in KLF2 repression.
  • To evaluate the therapeutic potential of restoring KLF2 expression.

Main Methods:

  • Analysis of EZH2 binding and histone modifications at the KLF2 gene locus.
  • Depletion of EZH2 using RNA interference, short hairpin RNA, and a small molecule inhibitor (3-Deazaneplanocin A).
  • In vitro and in vivo (xenograft mouse model) studies of KLF2 transfection and its effects on tumor growth, dissemination, and mortality.

Main Results:

  • EZH2 directly represses KLF2 transcription via epigenetic modifications (H3K27 trimethylation, RNA polymerase II phosphorylation).
  • EZH2 depletion restores KLF2 expression and exhibits significant anti-tumoral effects, reducing tumor growth, metastasis, and mortality.
  • KLF2 repression is crucial for EZH2-mediated oncogenesis, as KLF2 depletion partially rescues the oncogenic phenotype in EZH2-depleted cells.

Conclusions:

  • EZH2 epigenetically silences the tumor suppressor KLF2 in cancer cells.
  • Restoring KLF2 expression holds therapeutic promise for cancer treatment.
  • Low KLF2 and high EZH2 expression correlate with shorter survival in prostate and breast cancer patients.

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