title: HDAC2 deficiency sensitizes colon cancer cells to TNFalpha-induced apoptosis through inhibition of NF-kappaB activity.
abstract: HDAC inhibitors exert potent anti-tumorigenic and anti-inflammatory activity. Their effects are selective for transformed cells, and we recently demonstrated that transformation of epithelial cells with k-Ras sensitizes cells to HDACi induced apoptosis. The aim of this study was to determine whether the ability of HDACi to modulate signaling by a major pro-inflammatory cytokine, TNFalpha, is also restricted to cells that harbor mutant k-Ras. We used the system of two isogenic cell lines that differ by the presence of mutant k-Ras, HCT116 and Hke3 cells. Treatment of cells with TNFalpha alone did not induce apoptosis; however HDACi potentiated TNFalpha-induced apoptosis in both HCT116 and Hke3 cells. Thus, the ability of HDACi to sensitize cells to TNFalpha-induced apoptosis appears to be k-Ras independent. We demonstrated that HDACi inhibited TNFalpha-induced NF-kappaB transcriptional and DNA binding activity in both cell lines, underlying the increased apoptosis in cells treated with both agents. We showed that overexpression of HDAC2 enhanced TNFalpha-induced NF-kappaB activity and that silencing of HDAC2 decreased NF-kappaB activity. Finally, silencing of HDAC2 expression was sufficient to sensitize colon cancer cells to TNFalpha-induced apoptosis. The ability of HDACi to interfere with NF-kappaB activity is likely to contribute to their potent anti-tumorigenic and anti-inflammatory activity.
authors.affiliation: Department of Oncology, Albert Einstein Cancer Center, Montefiore Medical Center, Bronx, NY 10467, USA.
authors.forename: Pawan
authors.initials: P
authors.lastname: Kaler
authors.forename: Takehiko
authors.initials: T
authors.lastname: Sasazuki
authors.forename: Senji
authors.initials: S
authors.lastname: Shirasawa
authors.forename: Leonard
authors.initials: L
authors.lastname: Augenlicht
authors.forename: Lidija
authors.initials: L
authors.lastname: Klampfer
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D053453:Caspase 9 / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000473:pathology*; D004247:DNA / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020868:Gene Silencing / Q000187:drug effects; D045325:HCT116 Cells; D056464:Histone Deacetylase 2; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000172:deficiency*; D006801:Humans; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D012097:Repressor Proteins / Q000037:antagonists & inhibitors; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D051020:bcl-X Protein / Q000235:genetics; D018631:ras Proteins / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D016328:NF-kappa B; D012097:Repressor Proteins; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D051020:bcl-X Protein; D004247:DNA; D053453:Caspase 9; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases; D018631:ras Proteins