title: Involvement of HDAC1 and the PI3K/PKC signaling pathways in NF-kappaB activation by the HDAC inhibitor apicidin.
abstract: Histone deacetylase (HDAC) inhibitors are appreciated as one of promising anticancer drugs, but they exert differential responses depending on the cell type. We recently reported the critical role of NF-kappaB as a modulator in determining cell fate for apoptosis in response to an HDAC inhibitor. In this study, we investigate a possible signaling pathway required for NF-kappaB activation in response to the HDAC inhibitor apicidin. Treatment of HeLa cells with apicidin leads to an increase in transcriptional activity of NF-kappaB and the expression of its target genes, IL-8 and TNF-alpha. TNF-alpha expression by apicidin is induced at earlier time points than NF-kappaB activation or IL-8 expression. In addition, our data show that the early expression of TNF-alpha does not lead to activation of NF-kappaB, because disruption of TNF-alpha activity by a neutralizing antibody does not affect nuclear translocation of NF-kappaB, IkappaBalpha degradation or reporter gene activation by apicidin. However, this activation of NF-kappaB requires the PI3K and PKC signaling pathways, but not ERK or JNK. Furthermore, apicidin activation of NF-kappaB seems to result from HDAC1 inhibition, as evidenced by the observation that overexpression of HDAC1, but not HDAC2, 3 or 4, dramatically inhibits NF-kappaB reporter gene activity. Collectively, our results suggest that activation of NF-kappaB signaling by apicidin requires both the PI3K/PKC signaling pathways and HDAC1, and functions as a critical modulator in determining the cellular effect of apicidin.
authors.affiliation: Department of Pharmacology, Kwandong University College of Medicine, Gangneung 210-701, Republic of Korea. yksnbk@kwandong.ac.kr
authors.forename: Yong Kee
authors.initials: YK
authors.lastname: Kim
authors.forename: Dong-Wan
authors.initials: DW
authors.lastname: Seo
authors.forename: Dong-Won
authors.initials: DW
authors.lastname: Kang
authors.forename: Hoi Young
authors.initials: HY
authors.lastname: Lee
authors.forename: Jeung-Whan
authors.initials: JW
authors.lastname: Han
authors.forename: Su-Nam
authors.initials: SN
authors.lastname: Kim
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D002070:Butadienes / Q000494:pharmacology; D002867:Chromones / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D006367:HeLa Cells; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000096:biosynthesis / Q000502:physiology*; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis; D009025:Morpholines / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D011493:Protein Kinase C / Q000502:physiology*; D012097:Repressor Proteins / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D000077191:Wortmannin; D000099186:Histone Deacetylase 3
chemical_list: D000730:Androstadienes; D002070:Butadienes; D002867:Chromones; D005419:Flavonoids; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D016209:Interleukin-8; D009025:Morpholines; D016328:NF-kappa B; D009570:Nitriles; D010456:Peptides, Cyclic; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D012097:Repressor Proteins; D014409:Tumor Necrosis Factor-alpha; D000077191:Wortmannin; D000099186:Histone Deacetylase 3; C113580:U 0126; C102351:apicidin; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C110550:HDAC1 protein, human; C400300:HDAC4 protein, human; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one