Suberoylanilide hydroxamic acid increases anti-cancer effect of tumor necrosis factor-α through up-regulation of TNF receptor 1 in lung cancer cells

Oncotarget. 2017 Mar 14;8(11):17726-17737. doi: 10.18632/oncotarget.14628.


Suberoylanilide hydroxamic acid (SAHA) as a histone deacetylase (HDAC) inhibitor has anti-cancer effect. Here, we evaluated the effect of SAHA on HDAC activity and cell growth in many normal lung and cancer cells. We observed that the HDAC activities of lung cancer cells were higher than that of normal lung cells. SAHA inhibited the growth of lung cancer cells regardless of the inhibitory effect on HDAC. This agent induced a G2/M phase arrest and apoptosis, which was accompanied by mitochondrial membrane potential (MMP: ΔΨm) loss in lung cancer cells. However, SAHA did not induce cell death in normal lung cells. All tested caspase inhibitors prevented apoptotic cell death in SAHA-treated A549 and Calu-6 lung cancer cells. Treatment with tumor necrosis factor-alpha (TNF-α) enhanced apoptosis in SAHA-treated lung cancer cells through caspase-8 and caspase-9 activations. Especially, SAHA increased the expression level of TNF-α receptor 1 (TNFR1), especially acetylation of the region of TNFR1 promoter -223/-29 in lung cancer cells. The down-regulation of TNFR1 suppressed apoptosis in TNF-α and SAHA-treated lung cancer cells. In conclusion, SAHA inhibited the growth of lung cancer cells via a G2/M phase arrest and caspase-dependent apoptosis. SAHA also enhanced apoptotic effect of TNF-α in human lung cancer cells through up-regulation of TNFR1. TNF-α may be a key to improve anti-cancer effect of HDAC inhibitors.

Keywords: apoptosis; histone deacetylase; lung cancer; suberoylanilide hydroxamic acid; tumor necrosis factor-α.

MeSH terms

  • A549 Cells
  • Acetylation
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Caspase 8 / metabolism
  • Caspase 9 / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Enzyme Activation / drug effects
  • G2 Phase Cell Cycle Checkpoints / drug effects
  • Histone Deacetylase Inhibitors / pharmacology*
  • Histone Deacetylases / metabolism
  • Humans
  • Hydroxamic Acids / pharmacology*
  • Lung Neoplasms / pathology*
  • Membrane Potential, Mitochondrial / drug effects
  • Promoter Regions, Genetic / drug effects
  • Promoter Regions, Genetic / genetics
  • Receptors, Tumor Necrosis Factor, Type I / biosynthesis*
  • Receptors, Tumor Necrosis Factor, Type I / metabolism
  • Tumor Necrosis Factor-alpha / metabolism*
  • Up-Regulation
  • Vorinostat


  • Antineoplastic Agents
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Receptors, Tumor Necrosis Factor, Type I
  • Tumor Necrosis Factor-alpha
  • Vorinostat
  • Caspase 8
  • Caspase 9
  • Histone Deacetylases