EZH2/G9a interact to mediate drug resistance in non-small-cell lung cancer by regulating the SMAD4/ERK/c-Myc signaling axis
Qiuyue Zhang,
Yajie Shi,
Sen Liu,
Weiming Yang,
Huiping Chen,
Ning Guo,
Wanyu Sun,
Yongshan Zhao,
Yuxiang Ren,
Yong Ren,
Lina Jia,
Jingyu Yang,
Yi Yun,
Guoliang Chen,
Lihui Wang,
Chunfu Wu
Affiliations
Qiuyue Zhang
Department of Pharmacology, School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China
Yajie Shi
Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China
Sen Liu
Department of Pharmacology, School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China
Weiming Yang
Department of Pharmacology, School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China
Huiping Chen
Department of Pharmacology, School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China
Ning Guo
Department of Pharmacology, School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China
Wanyu Sun
Department of Pharmacology, School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China
Yongshan Zhao
Department of Biochemistry and Molecular Biology, School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China
Yuxiang Ren
Department of Biochemistry and Molecular Biology, School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China
Yong Ren
Department of Pathology, General Hospital of Central Theater Command of People’s Liberation Army, Wuhan 430070, China
Lina Jia
Department of Pharmacology, School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China
Jingyu Yang
Department of Pharmacology, School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China
Yi Yun
Biobank Center, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, China
Guoliang Chen
Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China; Corresponding author
Lihui Wang
Department of Pharmacology, School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China; Corresponding author
Chunfu Wu
Department of Pharmacology, School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China; Corresponding author
Summary: Drug resistance is the leading problem in non-small-cell lung cancer (NSCLC) therapy. The contribution of histone methylation in mediating malignant phenotypes of NSCLC is well known. However, the role of histone methylation in NSCLC drug-resistance mechanisms remains unclear. Here, our data show that EZH2 and G9a, two histone methyltransferases, are involved in the drug resistance of NSCLC. Gene manipulation results indicate that the combination of EZH2 and G9a promotes tumor growth and mediates drug resistance in a complementary manner. Importantly, clinical study demonstrates that co-expression of both enzymes predicts a poor outcome in patients with NSCLC. Mechanistically, G9a and EZH2 interact and promote the silencing of the tumor-suppressor gene SMAD4, activating the ERK/c-Myc signaling pathway. Finally, SU08, a compound targeting both EZH2 and G9a, is demonstrated to sensitize resistant cells to therapeutic drugs by regulating the SMAD4/ERK/c-Myc signaling axis. These findings uncover the resistance mechanism and a strategy for reversing NSCLC drug resistance.
