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

J Thorac Oncol. 2009 Dec;4(12):1455-65. doi: 10.1097/JTO.0b013e3181bc9419.


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.

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.

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.

Conclusions: These results support the role of ZEB proteins and HDAC inhibitors in the pathogenesis and treatment of lung cancer.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Benzamides / pharmacology
  • Benzoquinones / pharmacology
  • Blotting, Western
  • Cadherins / antagonists & inhibitors
  • Cadherins / genetics
  • Cadherins / metabolism*
  • Carcinoma, Non-Small-Cell Lung / metabolism*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Carcinoma, Non-Small-Cell Lung / prevention & control
  • Cell Proliferation / drug effects
  • Female
  • Flow Cytometry
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors
  • Histone Deacetylase Inhibitors / pharmacology
  • Histone Deacetylases / chemistry
  • Histone Deacetylases / metabolism
  • Homeodomain Proteins / antagonists & inhibitors
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • Hydroxamic Acids / pharmacology
  • Lactams, Macrocyclic / pharmacology
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / pathology
  • Lung Neoplasms / prevention & control
  • Pyridines / pharmacology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / pharmacology
  • Rats
  • Rats, Nude
  • Repressor Proteins / antagonists & inhibitors
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Tumor Cells, Cultured
  • Up-Regulation
  • Vorinostat
  • Zinc Finger E-box Binding Homeobox 2
  • Zinc Finger E-box-Binding Homeobox 1


  • Antineoplastic Agents
  • Benzamides
  • Benzoquinones
  • Cadherins
  • HSP90 Heat-Shock Proteins
  • Histone Deacetylase Inhibitors
  • Homeodomain Proteins
  • Hydroxamic Acids
  • Lactams, Macrocyclic
  • Pyridines
  • RNA, Messenger
  • RNA, Small Interfering
  • Repressor Proteins
  • Transcription Factors
  • ZEB1 protein, human
  • ZEB2 protein, human
  • Zinc Finger E-box Binding Homeobox 2
  • Zinc Finger E-box-Binding Homeobox 1
  • entinostat
  • trichostatin A
  • tanespimycin
  • Vorinostat
  • Histone Deacetylases