Abstract
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.
Highlights
Histone deacetylase (HDAC) triggers the suppression of transcription by removal of acetyl groups from lysine amino acid on histones [1]
It was observed that Calu-6, NCI-H1299 and small cell lung cancer (SCLC) cells showed higher histone deacetylase (HDAC) activities compared with normal lung and other lung cancer cells (Figure 1B)
Overexpression of HDAC2 is observed in lung cancer tissues [26]
Summary
Histone deacetylase (HDAC) triggers the suppression of transcription by removal of acetyl groups from lysine amino acid on histones [1]. Many studies have been demonstrated that the expression of HDAC is upregulated in many human cancers [2,3,4]. Diverse HDAC inhibitors are being studied in various cancers [5,6,7]. Suberoylanilide hydroxamic acid (SAHA) is the first HDAC inhibitor approved by U.S Food and Drug Administration for the treatment of cutaneous T-cell lymphoma. It has been clinically tested in lung and gastrointestinal cancers [8,9,10]. Numerous evidences indicate that SAHA induces apoptosis and inhibits metastasis in various cancer cells [11, 12]
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