title: Ineffectiveness of histone deacetylase inhibitors to induce apoptosis involves the transcriptional activation of NF-kappa B through the Akt pathway.
abstract: Histone deacetylase (HDAC) inhibitors are emerging as a new class of anticancer agents for the treatment of solid and hematological malignancies. Although HDAC inhibitors induce cell death through an apoptotic process, little is known about the molecular events that control their effectiveness. In this study, we demonstrate that HDAC inhibitors are limited in their ability to induce apoptosis in non-small cell lung cancer (NSCLC) cell lines despite their ability to effectively inhibit deacetylase activity. Because the anti-apoptotic transcription factor NF-kappa B has been shown to be under the control of HDAC-mediated repression, we analyzed whether HDAC inhibitors activated NF-kappa B in NSCLC cells. HDAC inhibitors effectively stimulated endogenous NF-kappa B-dependent gene expression by up-regulating IL-8, Bcl-XL, and MMP-9 transcripts. The ability of HDAC inhibitors to increase NF-kappa B transcriptional activity was not associated with signaling events that stimulated nuclear translocation, but rather modulated the transactivation potential of the RelA/p65 subunit of NF-kappa B. The inhibition of HDAC activity was associated with the recruitment of the p300 transcriptional co-activator to chromatin in an Akt-dependent manner. Moreover, Akt directly phosphorylated p300 in vitro and was required for stimulating the transactivation potential of the co-activator following the addition of HDAC inhibitors. Selective inhibition of either the phosphoinositide 3-kinase/Akt pathway, or NF-kappa B itself blocked the ability of HDAC inhibitors to activate NF-kappa B and dramatically sensitized NSCLC cells to apoptosis following of the addition of HDAC inhibitors. Our study indicates that the ineffectiveness of HDAC inhibitors to induce apoptosis in NSCLC cancer cells is associated with the ability of these molecules to stimulate NF-kappa B-dependent transcription and cell survival.
authors.affiliation: Department of Surgery, The University of Virginia, Charlottesville, Virginia 22908, USA.
authors.forename: Marty W
authors.initials: MW
authors.lastname: Mayo
authors.forename: Chadrick E
authors.initials: CE
authors.lastname: Denlinger
authors.forename: Robert M
authors.initials: RM
authors.lastname: Broad
authors.forename: Fan
authors.initials: F
authors.lastname: Yeung
authors.forename: Eugene T
authors.initials: ET
authors.lastname: Reilly
authors.forename: Yang
authors.initials: Y
authors.lastname: Shi
authors.forename: David R
authors.initials: DR
authors.lastname: Jones
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology; D002843:Chromatin / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005786:Gene Expression Regulation; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics; D008175:Lung Neoplasms / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D009687:Nuclear Proteins / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D051996:Transcription Factor RelA; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D051020:bcl-X Protein
chemical_list: D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; D002843:Chromatin; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D016209:Interleukin-8; D016328:NF-kappa B; D009687:Nuclear Proteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D015534:Trans-Activators; D051996:Transcription Factor RelA; D051020:bcl-X Protein; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020780:Matrix Metalloproteinase 9