VEGF/VEGFR-2 upregulates EZH2 expression in lung adenocarcinoma cells and EZH2 depletion enhances the response to platinum-based and VEGFR-2-targeted therapy.
OBJECTIVE
To investigate the mechanisms of regulation and role associated with enhancer of zeste homolog 2 (EZH2) expression in lung cancer cells.


METHODS
We investigated the mechanisms of EZH2 expression associated with the VEGF/VEGFR-2 pathway. Furthermore, we sought to determine the role of EZH2 in response of lung adenocarcinoma to platinum-based chemotherapy, as well as the effect of EZH2 depletion on VEGFR-2-targeted therapy in lung adenocarcinoma cell lines. In addition, we characterized EZH2 expression in lung adenocarcinoma specimens and correlated it with patients' clinical characteristics.


RESULTS
In this study, we demonstrate that VEGF/VEGFR-2 activation induces expression of EZH2 through the upregulation of E2F3 and hypoxia-inducible factor-1α (HIF1α), and downregulated expression of miR-101. EZH2 depletion by treatment with 3-deazaneplanocin A and knockdown by siRNA decreased the expression of EZH2 and H3K27me3, increased PARP-C level, reduced cell proliferation and migration, and increased sensitivity of the cells to treatment with cisplatin and carboplatin. In addition, high EZH2 expression was associated with poor overall survival in patients who received platinum-based adjuvant therapy, but not in patients who did not receive this therapy. Furthermore, we demonstrated for the first time that the inhibition of EZH2 greatly increased the sensitivity of lung adenocarcinoma cells to the anti-VEGFR-2 drug AZD2171.


CONCLUSIONS
Our results suggest that the VEGF/VEGFR-2 pathway plays a role in regulation of EZH2 expression via E2F3, HIF1α, and miR-101. EZH2 depletion decreases the malignant potential of lung adenocarcinoma and sensitivity of the cells to both platinum-based and VEGFR-2-targeted therapy.
Authors' Affiliations: Departments of Translational Molecular Pathology.
Erick
E
Riquelme
Thoracic/Head and Neck Medical Oncology.
Milind
M
Suraokar
Thoracic/Head and Neck Medical Oncology.
Carmen
C
Behrens
Biostatistics, and.
Heather Y
HY
Lin
Hamon Center for Therapeutic Oncology; Departments of Internal Medicine and Pharmacology, The University of Texas Southwestern Medical Center, Dallas, Texas.
Luc
L
Girard
Thoracic/Head and Neck Medical Oncology.
Monique B
MB
Nilsson
Thoracic/Head and Neck Medical Oncology.
George
G
Simon
Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston;
Jing
J
Wang
Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston;
Kevin R
KR
Coombes
Biostatistics, and.
J Jack
JJ
Lee
Thoracic/Head and Neck Medical Oncology.
Waun Ki
WK
Hong
Thoracic/Head and Neck Medical Oncology.
John
J
Heymach
Hamon Center for Therapeutic Oncology; Departments of Internal Medicine and Pharmacology, The University of Texas Southwestern Medical Center, Dallas, Texas.
John D
JD
Minna
Authors' Affiliations: Departments of Translational Molecular Pathology, Thoracic/Head and Neck Medical Oncology, iiwistuba@mdanderson.org.
Ignacio I
II
Wistuba
D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016190:Carboplatin / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002945:Cisplatin / Q000494:pharmacology; D000071221:Enhancer of Zeste Homolog 2 Protein; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D058990:Molecular Targeted Therapy; D063151:Polycomb Repressive Complex 2 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; C534072:MIRN101 microRNA, human; D035683:MicroRNAs; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C048460:3-deazaneplanocin; D016190:Carboplatin; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2; D000241:Adenosine; D002945:Cisplatin