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 language | English (US) |
|---|---|
| Pages (from-to) | 675-685 |
| Number of pages | 11 |
| Journal | Cancer Research |
| Volume | 76 |
| Issue number | 3 |
| DOIs | |
| State | Published - Feb 1 2016 |
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ASJC Scopus subject areas
- Cancer Research
- Oncology
Cite this
Modulation of EZH2 expression by MEK-ERK or PI3K-AKT signaling in lung cancer is dictated by different KRAS oncogene mutations. / Riquelme, Erick; Behrens, Carmen; Lin, Heather Y.; Simon, George; Papadimitrakopoulou, Vassiliki; Izzo, Julie; Moran, Cesar; Kalhor, Neda; Jack Lee, J.; Minna, John D.; Wistuba, Ignacio I.
In: Cancer Research, Vol. 76, No. 3, 01.02.2016, p. 675-685.Research output: Contribution to journal › Article
}
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.
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.
UR - http://www.scopus.com/inward/record.url?scp=84958231381&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84958231381&partnerID=8YFLogxK
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 - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0099-7013
IS - 3
ER -