Apoptotic sensitivity of colon cancer cells to histone deacetylase inhibitors is mediated by an Sp1/Sp3-activated transcriptional program involving immediate-early gene induction

Andrew J. Wilson, Anderly C. Chueh, Lars Tögel, Georgia A. Corner, Naseem Ahmed, Sanjay Goel, Do Sun Byun, Shannon Nasser, Michele A. Houston, Minaxi Jhawer, Helena J M Smartt, Lucas B. Murray, Courtney Nicholas, Barbara G. Heerdt, Diego Arango, Leonard H. Augenlicht, John M. Mariadason

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)609-620
Number of pages12
JournalCancer Research
Volume70
Issue number2
DOIs
StatePublished - Jan 15 2010

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Histone Deacetylase Inhibitors
Immediate-Early Genes
Colonic Neoplasms
Apoptosis
Sp3 Transcription Factor
Sp1 Transcription Factor
Genes
Gene Regulatory Networks
Computational Biology
Genetic Promoter Regions
Colon
Binding Sites
Gene Expression
Cell Line

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Apoptotic sensitivity of colon cancer cells to histone deacetylase inhibitors is mediated by an Sp1/Sp3-activated transcriptional program involving immediate-early gene induction. / Wilson, Andrew J.; Chueh, Anderly C.; Tögel, Lars; Corner, Georgia A.; Ahmed, Naseem; Goel, Sanjay; Byun, Do Sun; Nasser, Shannon; Houston, Michele A.; Jhawer, Minaxi; Smartt, Helena J M; Murray, Lucas B.; Nicholas, Courtney; Heerdt, Barbara G.; Arango, Diego; Augenlicht, Leonard H.; Mariadason, John M.

In: Cancer Research, Vol. 70, No. 2, 15.01.2010, p. 609-620.

Research output: Contribution to journalArticle

Wilson, AJ, Chueh, AC, Tögel, L, Corner, GA, Ahmed, N, Goel, S, Byun, DS, Nasser, S, Houston, MA, Jhawer, M, Smartt, HJM, Murray, LB, Nicholas, C, Heerdt, BG, Arango, D, Augenlicht, LH & Mariadason, JM 2010, 'Apoptotic sensitivity of colon cancer cells to histone deacetylase inhibitors is mediated by an Sp1/Sp3-activated transcriptional program involving immediate-early gene induction', Cancer Research, vol. 70, no. 2, pp. 609-620. https://doi.org/10.1158/0008-5472.CAN-09-2327
Wilson, Andrew J. ; Chueh, Anderly C. ; Tögel, Lars ; Corner, Georgia A. ; Ahmed, Naseem ; Goel, Sanjay ; Byun, Do Sun ; Nasser, Shannon ; Houston, Michele A. ; Jhawer, Minaxi ; Smartt, Helena J M ; Murray, Lucas B. ; Nicholas, Courtney ; Heerdt, Barbara G. ; Arango, Diego ; Augenlicht, Leonard H. ; Mariadason, John M. / Apoptotic sensitivity of colon cancer cells to histone deacetylase inhibitors is mediated by an Sp1/Sp3-activated transcriptional program involving immediate-early gene induction. In: Cancer Research. 2010 ; Vol. 70, No. 2. pp. 609-620.
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AU - Ahmed, Naseem

AU - Goel, Sanjay

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AU - Murray, Lucas B.

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