Apoptotic sensitivity of colon cancer cells to histone deacetylase inhibitors is mediated by an Sp1/Sp3-activated transcriptional program involving immediate-early gene induction.
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.
Wilson
Andrew J
AJ
Department of Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York, USA.
Chueh
Anderly C
AC
Tögel
Lars
L
Corner
Georgia A
GA
Ahmed
Naseem
N
Goel
Sanjay
S
Byun
Do-Sun
DS
Nasser
Shannon
S
Houston
Michele A
MA
Jhawer
Minaxi
M
Smartt
Helena J M
HJ
Murray
Lucas B
LB
Nicholas
Courtney
C
Heerdt
Barbara G
BG
Arango
Diego
D
Augenlicht
Leonard H
LH
Mariadason
John M
JM
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
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