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Title: The intestinal epithelial cell differentiation marker intestinal alkaline phosphatase (ALPi) is selectively induced by histone deacetylase inhibitors (HDACi) in colon cancer cells in a Kruppel-like factor 5 (KLF5)-dependent manner.
Austin Authors: Shin, Joongho;Carr, Azadeh;Corner, Georgia A;Tögel, Lars;Dávaos-Salas, Mercedes;Tran, Hoanh;Chueh, Anderly C;Al-Obaidi, Sheren;Chionh, Fiona;Ahmed, Naseem;Buchanan, Daniel D;Young, Joanne P;Malo, Madhu S;Hodin, Richard A;Arango, Diego;Sieber, Oliver M;Augenlicht, Leonard H;Dhillon, Amardeep S;Weber, Thomas K;Mariadason, John M 
Affiliation: the Walter and Eliza Hall Institute, Melbourne 3052, Australia
the Queensland Institute of Medical Research, 300 Herston Road, Herston, Queensland 4006, Australia
the Ludwig Institute for Cancer Research, Austin Health, Melbourne 3084, Australia
the Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02115.
the Group of Molecular Oncology, Centro en Investigación en Bioquímica y Biología Molecular-Nanomedicine, Vall d'Hebron University Hospital, Research Institute, Universitat Autònoma de Barcelona, Passeig Vall d'Hebron, 119-129, 08035 Barcelona, Spain and El Centro de Investigación Biomédica en Red de Bioingeniería, Biomateriales y Nanomedicina, Spain.
From the Department of Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York 10461.
Peter MacCallum Cancer Center, Melbourne 3002, Australia, and.
the Veterans Affairs New York Harbor Health Care System, Brooklyn, New York 11209.
From the Department of Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York 10461, the Ludwig Institute for Cancer Research, Austin Health, Melbourne 3084, Australia,
Issue Date: 18-Jul-2014
Publication information: The Journal of Biological Chemistry 2014; 289(36): 25306-16
Abstract: The histone deacetylase inhibitor (HDACi) sodium butyrate promotes differentiation of colon cancer cells as evidenced by induced expression and enzyme activity of the differentiation marker intestinal alkaline phosphatase (ALPi). Screening of a panel of 33 colon cancer cell lines identified cell lines sensitive (42%) and resistant (58%) to butyrate induction of ALP activity. This differential sensitivity was similarly evident following treatment with the structurally distinct HDACi, MS-275. Resistant cell lines were significantly enriched for those harboring the CpG island methylator phenotype (p = 0.036, Chi square test), and resistant cell lines harbored methylation of the ALPi promoter, particularly of a CpG site within a critical KLF/Sp regulatory element required for butyrate induction of ALPi promoter activity. However, butyrate induction of an exogenous ALPi promoter-reporter paralleled up-regulation of endogenous ALPi expression across the cell lines, suggesting the presence or absence of a key transcriptional regulator is the major determinant of ALPi induction. Through microarray profiling of sensitive and resistant cell lines, we identified KLF5 to be both basally more highly expressed as well as preferentially induced by butyrate in sensitive cell lines. KLF5 overexpression induced ALPi promoter-reporter activity in resistant cell lines, KLF5 knockdown attenuated butyrate induction of ALPi expression in sensitive lines, and butyrate selectively enhanced KLF5 binding to the ALPi promoter in sensitive cells. These findings demonstrate that butyrate induction of the cell differentiation marker ALPi is mediated through KLF5 and identifies subsets of colon cancer cell lines responsive and refractory to this effect.
DOI: 10.1074/jbc.M114.557546
Type: Journal Article
Subjects: CIMP
Colon Cancer
DNA Methylation
Histone Deacetylase Inhibitor (HDAC Inhibitor) (HDI)
Kruppel-like Factor (KLF)
Alkaline Phosphatase.genetics.metabolism
Binding Sites.genetics
Blotting, Western
Butyric Acid.pharmacology
Cell Differentiation.drug effects.genetics
Cell Line, Tumor
Colonic Neoplasms.genetics.metabolism.pathology
CpG Islands.genetics
Drug Resistance, Neoplasm.genetics
Epithelial Cells.metabolism
Gene Expression Profiling
HCT116 Cells
HT29 Cells
Histone Deacetylase Inhibitors.pharmacology
Kruppel-Like Transcription Factors.genetics.metabolism
Oligonucleotide Array Sequence Analysis
Promoter Regions, Genetic.genetics
Protein Binding
Reverse Transcriptase Polymerase Chain Reaction
Appears in Collections:Journal articles

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