Abstract
Mesalazine (5-ASA) is an aminosalicylate anti-inflammatory drug capable of inducing μ-protocadherin, a protein expressed by colorectal epithelial cells which 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.
- Received November 27, 2017.
- Revision received April 10, 2018.
- Accepted May 16, 2018.
- Copyright ©2018, American Association for Cancer Research.
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Published OnlineFirst May 24, 2018
doi: 10.1158/1940-6207.CAPR-17-0382
