Modulation of EZH2 expression by MEK-ERK or PI3K-AKT signaling in lung cancer is dictated by different KRAS oncogene mutations

Erick Riquelme, Carmen Behrens, Heather Y. Lin, George Simon, Vassiliki Papadimitrakopoulou, Julie Izzo, Cesar Moran, Neda Kalhor, J. Jack Lee, John D. Minna, Ignacio I. Wistuba

Research output: Contribution to journalArticle

51 Scopus citations

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 KRASG12C and KRASG12D mutations, EZH2 expression was modulated by MEK-ERK and PI3K/AKT signaling, respectively. Accordingly, MEK-ERK depletion decreased EZH2 expression in cells harboring the KRASG12C mutation, whereas PI3K/AKT depletion decreased EZH2 expression, EZH2 phosphorylation, and STAT3 activity in KRASG12D-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.

Original languageEnglish (US)
Pages (from-to)675-685
Number of pages11
JournalCancer Research
Volume76
Issue number3
DOIs
StatePublished - Feb 1 2016

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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    Riquelme, E., Behrens, C., Lin, H. Y., Simon, G., Papadimitrakopoulou, V., Izzo, J., Moran, C., Kalhor, N., Jack Lee, J., Minna, J. D., & Wistuba, I. I. (2016). Modulation of EZH2 expression by MEK-ERK or PI3K-AKT signaling in lung cancer is dictated by different KRAS oncogene mutations. Cancer Research, 76(3), 675-685. https://doi.org/10.1158/0008-5472.CAN-15-1141