title: Modulation of EZH2 Expression by MEK-ERK or PI3K-AKT Signaling in Lung Cancer Is Dictated by Different KRAS Oncogene Mutations.
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.
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer, Houston, Texas.
authors.forename: Erick
authors.initials: E
authors.lastname: Riquelme
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Carmen
authors.initials: C
authors.lastname: Behrens
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer, Houston, Texas.
authors.forename: Heather Y
authors.initials: HY
authors.lastname: Lin
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: George
authors.initials: G
authors.lastname: Simon
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Papadimitrakopoulou
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer, Houston, Texas.
authors.forename: Julie
authors.initials: J
authors.lastname: Izzo
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer, Houston, Texas.
authors.forename: Cesar
authors.initials: C
authors.lastname: Moran
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer, Houston, Texas.
authors.forename: Neda
authors.initials: N
authors.lastname: Kalhor
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer, Houston, Texas.
authors.forename: J Jack
authors.initials: JJ
authors.lastname: Lee
authors.affiliation: Hamon Center for Therapeutic Oncology, The University of Texas Southwestern Medical Center, Dallas, Texas. Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas. Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: John D
authors.initials: JD
authors.lastname: Minna
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer, Houston, Texas. Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. iiwistuba@mdanderson.org.
authors.forename: Ignacio I
authors.initials: II
authors.lastname: Wistuba
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism*; D000077192:Adenocarcinoma of Lung; D000818:Animals; D045744:Cell Line, Tumor; D000071221:Enhancer of Zeste Homolog 2 Protein; D005260:Female; D011905:Genes, ras; D064593:Heterografts; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D063151:Polycomb Repressive Complex 2 / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D019869:Phosphatidylinositol 3-Kinases; D018631:ras Proteins