title: HDAC6 promotes cell proliferation and confers resistance to gefitinib in lung adenocarcinoma.
abstract: Histone deacetylases (HDACs) are promising targets for cancer therapy, and first-generation HDAC inhibitors are currently in clinical trials for the treatment of cancer patients. HDAC6, which is a key regulator of many signaling pathways that are linked to cancer, has recently emerged as an attractive target for the treatment of cancer. In the present study, HDAC6 was found to be overexpressed in lung adenocarcinoma cell lines and was negatively correlated with the prognosis of patients with lung adenocarcinoma. Overexpression of HDAC6 promoted the proliferation of lung adenocarcinoma cells in a deacetylase activity-dependent manner. HDAC6 overexpression conferred resistance to gefitinib via the stabilization of epidermal growth factor receptor (EGFR). The inhibition of HDAC6 by CAY10603, a potent and selective inhibitor of HDAC6, inhibited the proliferation of lung adenocarcinoma cells and induced apoptosis. CAY10603 downregulated the levels of EGFR protein, which in turn inhibited activation of the EGFR signaling pathway. Moreover, CAY10603 synergized with gefitinib to induce apoptosis of the lung adenocarcinoma cell lines via the destabilization of EGFR. Taken together, our results suggest that the inhibition of HDAC6 may be a promising strategy for the treatment of lung adenocarcinoma.
authors.affiliation: Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuchang, Wuhan 430071, P.R. China.
authors.forename: Zhihao
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuchang, Wuhan 430071, P.R. China.
authors.forename: Fang
authors.initials: F
authors.lastname: Tang
authors.affiliation: Department of Pathology and Pathophysiology, School of Basic Medical Sciences, Wuhan University, Wuchang, Wuhan 430071, P.R. China.
authors.forename: Pengchao
authors.initials: P
authors.lastname: Hu
authors.affiliation: Department of Pathology and Pathophysiology, School of Basic Medical Sciences, Wuhan University, Wuchang, Wuhan 430071, P.R. China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuchang, Wuhan 430071, P.R. China.
authors.forename: Jun
authors.initials: J
authors.lastname: Gong
authors.affiliation: Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuchang, Wuhan 430071, P.R. China.
authors.forename: Shaoxing
authors.initials: S
authors.lastname: Sun
authors.affiliation: Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuchang, Wuhan 430071, P.R. China.
authors.forename: Conghua
authors.initials: C
authors.lastname: Xie
mesh_terms: D000072283:A549 Cells; D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics*; D000077192:Adenocarcinoma of Lung; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics*; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000235:genetics; D000077156:Gefitinib; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D066246:ErbB Receptors; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; D000077156:Gefitinib