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RAS oncogenic signal upregulates EZH2 in pancreatic cancer

Satoshi Fujii1, Katsumi Fukamachi, Hiroyuki Tsuda

  • 1Pathology Division, Research Center for Innovative Oncology, Chiba, Japan.

Biochemical and Biophysical Research Communications
|January 7, 2012
PubMed

Insights

Oncogenic RAS upregulates EZH2, a histone modifier, initiating pancreatic cancer. Inhibiting EZH2 or MEK-ERK signaling restores tumor suppressors like RUNX3 and halts cancer growth.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Neoplastic transformation by mutant RAS involves gene expression remodeling.
  • The initiation mechanism for this gene expression remodeling in tumorigenesis is unclear.
  • EZH2, a histone modifier, is induced by oncogenic RAS.

Purpose of the Study:

  • To define the oncogenic role of EZH2 in pancreatic carcinogenesis.
  • To investigate the mechanism by which mutant RAS induces EZH2.
  • To explore EZH2's impact on tumor suppressor genes and cancer cell growth.

Main Methods:

  • Utilized a transgenic rat model expressing human mutant RAS.
  • Performed immunohistochemical analysis of preneoplastic and cancerous lesions.
  • Employed MEK-inhibition, Elk-1-knockdown, and EZH2-knockdown in human and rat pancreatic cancer cells.

Main Results:

  • Upregulation of EZH2 protein was identified as an initiating event in pancreatic carcinogenesis.
  • MEK-ERK signaling pathway mediates RAS-induced EZH2 upregulation.
  • MEK inhibition or EZH2 knockdown restored RUNX3 tumor suppressor expression and inhibited cancer cell growth.

Conclusions:

  • Oncogenic RAS upregulates EZH2 via MEK-ERK signaling, initiating pancreatic carcinogenesis.
  • EZH2 downregulation of tumor suppressors, including RUNX3, is a key mechanism in pancreatic cancer.
  • Targeting EZH2 or the MEK-ERK pathway may offer therapeutic strategies for pancreatic cancer.

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