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Induction of E-cadherin in lung cancer and interaction with growth suppression by histone deacetylase inhibition.

Authors :
Kakihana M
Ohira T
Chan D
Webster RB
Kato H
Drabkin HA
Gemmill RM
Source :
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer [J Thorac Oncol] 2009 Dec; Vol. 4 (12), pp. 1455-65.
Publication Year :
2009

Abstract

Introduction: Loss of E-cadherin confers a poor prognosis in lung cancer patients and is associated with in vitro resistance to endothelial growth factor receptor inhibitors. Zinc finger E box-binding homeobox (ZEB)-1, the predominant transcriptional suppressor of E-cadherin in lung tumor lines, recruits histone deacetylases (HDACs) as co-repressors.<br />Methods: NSCLC cell lines were treated with HDAC inhibitors and analyzed for E-cadherin induction, growth inhibition and apoptosis. National Cancer Institute-H157 cells expressing ectopic E-cadherin were tested for tumorigenicity in murine xenografts.<br />Results: We found that treatment with MS-275, compared to vorinostat (SAHA), valproic acid or trichostatin A, was most effective in E-cadherin up-regulation and persistence in non-small cell lung cancers. As with other tumor types and HDAC inhibitors, MS-275 inhibited growth and induced apoptosis. Importantly, blocking E-cadherin induction by short hairpin RNA resulted in less inhibition by MS-275, implicating the epithelial to mesenchymal phenotype process as a contributing factor. In contrast to H460 and H661, H157 cells were resistant to E-cadherin up-regulation by HDAC inhibitors. However, E-cadherin was restored, in a synergistic manner, by combined knockdown of ZEB-1 and ZEB-2. In addition, H157 cells stably transfected with E-cadherin were markedly attenuated in their tumor forming ability. Lastly, combining MS-275 with the microtubule stabilizing agent, paclitaxel, or 17-(allylamino)-17-demethoxygeldanamycin, a heat shock protein 90 inhibitor, resulted in synergistic growth inhibition. Since MS-275 has no reported activity against HDAC6, which regulates both microtubule and heat shock protein 90 functions, other mechanisms of synergy are anticipated.<br />Conclusions: These results support the role of ZEB proteins and HDAC inhibitors in the pathogenesis and treatment of lung cancer.

Details

Language :
English
ISSN :
1556-1380
Volume :
4
Issue :
12
Database :
MEDLINE
Journal :
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
Publication Type :
Academic Journal
Accession number :
20009910
Full Text :
https://doi.org/10.1097/JTO.0b013e3181bc9419