title: Apoptotic sensitivity of colon cancer cells to histone deacetylase inhibitors is mediated by an Sp1/Sp3-activated transcriptional program involving immediate-early gene induction.
abstract: Histone deacetylase inhibitors (HDACi) induce growth arrest and apoptosis in colon cancer cells and are being considered for colon cancer therapy. The underlying mechanism of action of these effects is poorly defined with both transcription-dependent and -independent mechanisms implicated. We screened a panel of 30 colon cancer cell lines for sensitivity to HDACi-induced apoptosis and correlated the differences with gene expression patterns induced by HDACi in the five most sensitive and resistant lines. A robust and reproducible transcriptional response involving coordinate induction of multiple immediate-early (fos, jun, egr1, egr3, atf3, arc, nr4a1) and stress response genes (Ndrg4, Mt1B, Mt1E, Mt1F, Mt1H) was selectively induced in HDACi sensitive cells. Notably, a significant percentage of these genes were basally repressed in colon tumors. Bioinformatics analysis revealed that the promoter regions of the HDACi-induced genes were enriched for KLF4/Sp1/Sp3 transcription factor binding sites. Altering KLF4 levels failed to modulate apoptosis or transcriptional responses to HDACi treatment. In contrast, HDACi preferentially stimulated the activity of Spl/Sp3 and blocking their action attenuated both the transcriptional and apoptotic responses to HDACi treatment. Our findings link HDACi-induced apoptosis to activation of a Spl/Sp3-mediated response that involves derepression of a transcriptional network basally repressed in colon cancer.
authors.affiliation: Department of Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Wilson
authors.forename: Anderly C
authors.initials: AC
authors.lastname: Chueh
authors.forename: Lars
authors.initials: L
authors.lastname: Tögel
authors.forename: Georgia A
authors.initials: GA
authors.lastname: Corner
authors.forename: Naseem
authors.initials: N
authors.lastname: Ahmed
authors.forename: Sanjay
authors.initials: S
authors.lastname: Goel
authors.forename: Do-Sun
authors.initials: DS
authors.lastname: Byun
authors.forename: Shannon
authors.initials: S
authors.lastname: Nasser
authors.forename: Michele A
authors.initials: MA
authors.lastname: Houston
authors.forename: Minaxi
authors.initials: M
authors.lastname: Jhawer
authors.forename: Helena J M
authors.initials: HJ
authors.lastname: Smartt
authors.forename: Lucas B
authors.initials: LB
authors.lastname: Murray
authors.forename: Courtney
authors.initials: C
authors.lastname: Nicholas
authors.forename: Barbara G
authors.initials: BG
authors.lastname: Heerdt
authors.forename: Diego
authors.initials: D
authors.lastname: Arango
authors.forename: Leonard H
authors.initials: LH
authors.lastname: Augenlicht
authors.forename: John M
authors.initials: JM
authors.lastname: Mariadason
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D001665:Binding Sites; D002087:Butyrates / Q000494:pharmacology; D018938:Caco-2 Cells; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D003609:Dactinomycin / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D017781:Genes, Immediate-Early / Q000187:drug effects*; D045325:HCT116 Cells; D019073:HT29 Cells; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D016329:Sp1 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D051705:Sp3 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D002087:Butyrates; D056572:Histone Deacetylase Inhibitors; C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; C497121:SP3 protein, human; D016329:Sp1 Transcription Factor; D051705:Sp3 Transcription Factor; D003609:Dactinomycin