Inhibition of EZH2 reverses chemotherapeutic drug TMZ chemosensitivity in glioblastoma.
Glioblastoma remains among the most devastating cancers with a median survival of less than 15 months and virtually no survival beyond five years. Currently, the treatment of glioma includes surgery, radiation therapy, chemotherapy, and comprehensive treatment. Intrinsic or acquired resistance to TMZ, is one of the greatest obstacles in successful GB treatment, and is thought to be influenced by a variety of mechanisms. The EZH2 gene, which is expressed in various solid tumors, can regulate gene transcription and promote the generation and progression of tumors. Our aim was to investigate the relationship between EZH2 and multidrug-resistance of human glioblastoma cells. In this study, we established TMZ-resistant U251 and U87 clones (U251/TMZ and U87/TMZ cells), which expressed high level of EZH2. Using RNA interference, we demonstrated that the downregulation of Ezh2 expression in U251/TMZ and U87/TMZ cells resulted in apoptosis and a cell cycle arrest in the G1/S phase. Furthermore, the reduced expression of Ezh2 altered the MDR, MRP and BCRP mRNA and protein levels. These findings suggest that EZH2 plays an important part in the development of multidrug resistance and may represent a novel therapeutic target for multidrug-resistant glioblastoma.
Department of Neurosurgery, Nan-Fang Hospital of Southern Medical University Guangzhou 510515, P.R. China ; Department of Neurosurgery, Chang-Sha Central Hospital Changsha 410004, Hunan, P.R. China.
Tian-Yu
TY
Fan
Department of Neurosurgery, Nan-Fang Hospital of Southern Medical University Guangzhou 510515, P.R. China.
Hai
H
Wang
Department of Neurosurgery, Chang-Sha Central Hospital Changsha 410004, Hunan, P.R. China.
Peng
P
Xiang
Department of Neurosurgery, Nan-Fang Hospital of Southern Medical University Guangzhou 510515, P.R. China.
Ya-Wei
YW
Liu
Department of Neurosurgery, Nan-Fang Hospital of Southern Medical University Guangzhou 510515, P.R. China.
He-Zhen
HZ
Li
Department of Neurosurgery, Nan-Fang Hospital of Southern Medical University Guangzhou 510515, P.R. China.
Bing-Xi
BX
Lei
Department of Neurosurgery, Nan-Fang Hospital of Southern Medical University Guangzhou 510515, P.R. China.
Meng
M
Yu
Department of Neurosurgery, Nan-Fang Hospital of Southern Medical University Guangzhou 510515, P.R. China.
Song-Tao
ST
Qi
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D000071221:Enhancer of Zeste Homolog 2 Protein; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D063151:Polycomb Repressive Complex 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D000077204:Temozolomide; D013997:Time Factors; D014162:Transfection
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D018906:Antineoplastic Agents, Alkylating; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D003606:Dacarbazine; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D000077204:Temozolomide
EZH2; Glioblastoma; multidrug-resistance; therapeutic target