Modulation of EZH2 Expression by MEK-ERK or PI3K-AKT Signaling in Lung Cancer Is Dictated by Different KRAS Oncogene Mutations

Cancer Res. 2016 Feb 1;76(3):675-85. doi: 10.1158/0008-5472.CAN-15-1141. Epub 2015 Dec 16.

Abstract

EZH2 overexpression promotes cancer by increasing histone methylation to silence tumor suppressor genes, but how EZH2 levels become elevated in cancer is not understood. In this study, we investigated the mechanisms by which EZH2 expression is regulated in non-small cell lung carcinoma cells by oncogenic KRAS. In cells harboring KRAS(G12C) and KRAS(G12D) mutations, EZH2 expression was modulated by MEK-ERK and PI3K/AKT signaling, respectively. Accordingly, MEK-ERK depletion decreased EZH2 expression in cells harboring the KRAS(G12C) mutation, whereas PI3K/AKT depletion decreased EZH2 expression, EZH2 phosphorylation, and STAT3 activity in KRAS(G12D)-mutant cell lines. Combined inhibition of EZH2 and MEK-ERK or PI3K/AKT increased the sensitivity of cells with specific KRAS mutations to MEK-ERK and PI3K/AKT-targeted therapies. Our work defines EZH2 as a downstream effector of KRAS signaling and offers a rationale for combining EZH2 inhibitory strategies with MEK-ERK- or PI3K/AKT-targeted therapies to treat lung cancer patients, as stratified into distinct treatment groups based on specific KRAS mutations.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenocarcinoma / genetics
  • Adenocarcinoma / metabolism*
  • Adenocarcinoma of Lung
  • Animals
  • Cell Line, Tumor
  • Enhancer of Zeste Homolog 2 Protein
  • Female
  • Genes, ras*
  • Heterografts
  • Humans
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism*
  • MAP Kinase Signaling System*
  • Mice
  • Mice, Nude
  • Mutation*
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphorylation
  • Polycomb Repressive Complex 2 / biosynthesis*
  • Polycomb Repressive Complex 2 / genetics*
  • Polycomb Repressive Complex 2 / metabolism
  • Transfection
  • ras Proteins / genetics
  • ras Proteins / metabolism

Substances

  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein
  • Polycomb Repressive Complex 2
  • Phosphatidylinositol 3-Kinases
  • ras Proteins