title: Depletion of HDAC6 enhances cisplatin-induced DNA damage and apoptosis in non-small cell lung cancer cells.
abstract: Histone deacetylase inhibitors (HDACi) are promising therapeutic agents which are currently used in combination with chemotherapeutic agents in clinical trials for cancer treatment including non-small cell lung cancer (NSCLC). However, the mechanisms underlying their anti-tumor activities remain elusive. Previous studies showed that inhibition of HDAC6 induces DNA damage and sensitizes transformed cells to anti-tumor agents such as etoposide and doxorubicin. Here, we showed that depletion of HDAC6 in two NSCLC cell lines, H292 and A549, sensitized cells to cisplatin, one of the first-line chemotherapeutic agents used to treat NSCLC. We suggested that depletion of HDAC6 increased cisplatin-induced cytotoxicity was due to the enhancement of apoptosis via activating ATR/Chk1 pathway. Furthermore, we showed that HDAC6 protein levels were positively correlated with cisplatin IC(50) in 15 NSCLC cell lines. Lastly, depletion of HDAC6 in H292 xenografts rendered decreased tumor weight and volume and exhibited increased basal apoptosis compared with the controls in a xenograft mouse model. In summary, our findings suggest that HDAC6 is positively associated with cisplatin resistance in NSCLC and reveal HDAC6 as a potential novel therapeutic target for platinum refractory NSCLC.
authors.affiliation: Department of Pathology and Cell Biology, University of South Florida, Morsani College of Medicine, Tampa, Florida, United States of America.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.forename: Shengyan
authors.initials: S
authors.lastname: Xiang
authors.forename: Kendra A
authors.initials: KA
authors.lastname: Williams
authors.forename: Huiqin
authors.initials: H
authors.lastname: Dong
authors.forename: Wenlong
authors.initials: W
authors.lastname: Bai
authors.forename: Santo V
authors.initials: SV
authors.lastname: Nicosia
authors.forename: Saadi
authors.initials: S
authors.lastname: Khochbin
authors.forename: Gerold
authors.initials: G
authors.lastname: Bepler
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D020552:Comet Assay; D004249:DNA Damage; D004317:Doxorubicin / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000235:genetics* / Q000502:physiology*; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry / Q000379:methods; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology
chemical_list: D013778:Tetrazolium Salts; D013844:Thiazoles; D005047:Etoposide; D004317:Doxorubicin; C433811:HDAC6 protein, human; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; C022616:thiazolyl blue; D002945:Cisplatin