KLF4 Mediates the Effect of 5-ASA on the β-Catenin Pathway in Colon Cancer Cells

Sandra Parenti; Lucia Montorsi; Sebastian Fantini; Fabiana Mammoli; Claudia Gemelli; Claudio Giacinto Atene; Lorena Losi; Chiara Frassineti; Bruno Calabretta; Enrico Tagliafico; Sergio Ferrari; Tommaso Zanocco-Marani; Alexis Grande

doi:10.1158/1940-6207.CAPR-17-0382

KLF4 Mediates the Effect of 5-ASA on the β-Catenin Pathway in Colon Cancer Cells

Cancer Prev Res (Phila). 2018 Aug;11(8):503-510. doi: 10.1158/1940-6207.CAPR-17-0382. Epub 2018 May 24.

Authors

Affiliations

¹ Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy.
² Center for Genome Research, University of Modena and Reggio Emilia, Modena, Italy.
³ Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
⁴ Science and Technology Park for Medicine, Mirandola, Modena, Italy.
⁵ Department of Biomedical Sciences, University of Modena and Reggio Emilia, Modena, Italy.
⁶ Department of Clinical and Diagnostic Medicine and Public Health, University of Modena and Reggio Emilia, Modena, Italy.
⁷ Department of Cancer Biology and SKKC, Thomas Jefferson University, Philadelphia, Pennsylvania.
⁸ Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy. alexis.grande@unimore.it.

PMID: 29794245
DOI: 10.1158/1940-6207.CAPR-17-0382

Abstract

Mesalazine (5-ASA) is an aminosalicylate anti-inflammatory drug capable of inducing μ-protocadherin, a protein expressed by colorectal epithelial cells that is downregulated upon malignant transformation. Treatment with 5-ASA restores μ-protocadherin expression and promotes the sequestration of β-catenin to the plasma membrane. Here, we show that 5-ASA-induced μ-protocadherin expression is directly regulated by the KLF4 transcription factor. In addition, we suggest the existence of a dual mechanism whereby 5-ASA-mediated β-catenin inhibition is caused by μ-protocadherin-dependent sequestration of β-catenin to the plasma membrane and by the direct binding of KLF4 to β-catenin. In addition, we found that 5-ASA treatment suppresses the expression of miR-130a and miR-135b, which target KLF4 mRNA, raising the possibility that this mechanism is involved in the increased expression of KLF4 induced by 5-ASA. Cancer Prev Res; 11(8); 503-10. ©2018 AACR.

MeSH terms

Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
Anti-Inflammatory Agents, Non-Steroidal / therapeutic use
Caco-2 Cells
Cadherin Related Proteins
Cadherins / metabolism
Cell Membrane / drug effects
Cell Membrane / metabolism
Colonic Neoplasms / genetics
Colonic Neoplasms / pathology
Colonic Neoplasms / prevention & control*
Down-Regulation / drug effects
Gene Expression Regulation, Neoplastic / drug effects
HEK293 Cells
HT29 Cells
Humans
Kruppel-Like Factor 4
Kruppel-Like Transcription Factors / genetics
Kruppel-Like Transcription Factors / metabolism*
Mesalamine / pharmacology*
Mesalamine / therapeutic use
MicroRNAs / metabolism
Protein Binding / drug effects
Up-Regulation / drug effects
Wnt Signaling Pathway / drug effects*
Wnt Signaling Pathway / genetics
beta Catenin / metabolism

Substances

Anti-Inflammatory Agents, Non-Steroidal
CDHR5 protein, human
CTNNB1 protein, human
Cadherin Related Proteins
Cadherins
KLF4 protein, human
Kruppel-Like Factor 4
Kruppel-Like Transcription Factors
MIRN130 microRNA, human
MIRN135 microRNA, human
MicroRNAs
beta Catenin
Mesalamine