KLF4‐dependent, PPARγ‐induced expression of GPA33 in colon cancer cell lines
Open Access
- 23 June 2009
- journal article
- research article
- Published by Wiley in International Journal of Cancer
- Vol. 125 (12), 2802-2809
- https://doi.org/10.1002/ijc.24683
Abstract
The glycoprotein A33 (GPA33) is a colon cancer antigen. Phase I trials with 131I and 125I monoclonal antibody A33 in colon carcinoma patients showed excellent localization to colorectal cancer and some evidence of tumor response. Using DNA microarrays, we have identified the GPA33 gene as a target of PPARγ in HT29‐Cl.16E colon cancer cells. Treatment of HT29‐Cl.16E, Caco2, SW1116 and LS174T colon cancer cells with the PPARγ agonist GW7845 induced a 2‐ to 6‐fold increase in GPA33 mRNA as determined by real‐time PCR. This induction was also found in HT29‐Cl.16E cells treated with rosiglitazone and ciglitazone and was prevented by cotreatment with the PPARγ antagonist GW9662, indicating that this regulation was PPARγ dependent. No canonical PPAR responsive element was found in the GPA33 promoter. We therefore analyzed the expression of transcription factors involved in GPA33 expression. CDXl, CDX2 and KLF5 expression was not modified by PPARγ activation. By contrast, a significant increase in KLF4 was seen, both at mRNA and protein levels. Furthermore, chromatin immunoprecipitation studies demonstrated that an increased amount of KLF4 protein was bound to the GPA33 promoter in cells treated with rosiglitazone. Finally, downregulation of KLF4 expression by siRNA reduced rosiglitazone‐induced GPA33 expression. This indicates that PPARγ activation induces KLF4 expression, which in turn increases GPA33 expression. We also demonstrate that PPARγ activation leads to increased (p21WAF1/Cip1 and keratin 19) or decreased (cyclin D1) expression of known KLF4 targets, suggesting that KLF4 is a nodal player in a network of PPARγ‐regulated genes. © 2009 UICCThis publication has 59 references indexed in Scilit:
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