TY - JOUR
T1 - Modulation of EZH2 expression by MEK-ERK or PI3K-AKT signaling in lung cancer is dictated by different KRAS oncogene mutations
AU - Riquelme, Erick
AU - Behrens, Carmen
AU - Lin, Heather Y.
AU - Simon, George
AU - Papadimitrakopoulou, Vassiliki
AU - Izzo, Julie
AU - Moran, Cesar
AU - Kalhor, Neda
AU - Jack Lee, J.
AU - Minna, John D.
AU - Wistuba, Ignacio I.
N1 - Funding Information:
This study was supported part by a Department of Defense PROSPECT grant (W81XWH-07-1-0306 to I.I. Wistuba and J.D. Minna); the UT Lung Specialized Programs of Research Excellence grant P50CA70907 from the NIH NCI (I.I. Wistuba and J.D. Minna); R01 CA155196 (I.I. Wistuba and V. Papadimitrakopoulou) from the NIH NCI; Cancer Prevention Research Institute of Texas (CPRIT) grant RP110708 (I.I. Wistuba); and MD Anderson''s Institutional Tissue Bank 2P30CA016672 from the NIH NCI. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Publisher Copyright:
© 2015 American Association for Cancer Research.
PY - 2016/2/1
Y1 - 2016/2/1
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-15-1141
DO - 10.1158/0008-5472.CAN-15-1141
M3 - Article
C2 - 26676756
AN - SCOPUS:84958231381
VL - 76
SP - 675
EP - 685
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 3
ER -