HDAC6 promotes cell proliferation and confers resistance to temozolomide in glioblastoma.
Histone deacetylases are considered to be among the most promising targets in drug development for cancer therapy. Histone deacetylase 6 (HDAC6) is a unique cytoplasmic enzyme that regulates many biological processes involved in tumorigenesis through its deacetylase and ubiquitin-binding activities. Here, we report that HDAC6 is overexpressed in glioblastoma tissues and cell lines. Overexpression of HDAC6 promotes the proliferation and spheroid formation of glioblastoma cells. HDAC6 overexpression confers resistance to temozolomide (TMZ) mediated cell proliferation inhibition and apoptosis induction. Conversely, knockdown of HDAC6 inhibits cell proliferation, impairs spheroid formation and sensitizes glioblastoma cells to TMZ. The inhibition of HDAC6 deacetylase activity by selective inhibitors inhibits the proliferation of glioblastoma cells and induces apoptosis. HDAC6 selective inhibitors can sensitize glioblastoma cells to TMZ. Moreover, we showed that HDAC6 mediated EGFR stabilization might partly account for its oncogenic role in glioblastoma. TMZ resistant glioblastoma cells showed higher expression of HDAC6 and more activation of EGFR. HDAC6 inhibitors decrease EGFR protein levels and impair the activation of the EGFR pathway. Taken together, our results suggest that the inhibition of HDAC6 may be a promising strategy for the treatment of glioblastoma.
Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China; School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China.
Zhihao
Z
Wang
School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China.
Pengchao
P
Hu
Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China.
Fang
F
Tang
Department of Neurosurgery, Wuhan University Renmin Hospital, Wuhan 430060, China.
Haiwei
H
Lian
School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China.
Xiong
X
Chen
School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China.
Yingying
Y
Zhang
School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China.
Xiaohua
X
He
School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China. Electronic address: liuwanhong@whu.edu.cn.
Wanhong
W
Liu
Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China. Electronic address: chxie_65@whu.edu.cn.
Conghua
C
Xie
D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D066246:ErbB Receptors / Q000187:drug effects / Q000378:metabolism; D005909:Glioblastoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D055550:Protein Stability; D015398:Signal Transduction / Q000187:drug effects; D000077204:Temozolomide; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation
D018906:Antineoplastic Agents, Alkylating; D056572:Histone Deacetylase Inhibitors; D003606:Dacarbazine; C512478:EGFR protein, human; D066246:ErbB Receptors; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; D000077204:Temozolomide
EGFR; Glioblastoma; HDAC6; Temozolomide