Advisory Committee Chair
J Michael Ruppert
Advisory Committee Members
Susan M Lobo-Ruppert
Weei-Chin Lin
Donald D Muccio
Susan Nozell
Natalia Y Kedishvili
Document Type
Dissertation
Date of Award
2009
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
The fight against cancer has generated wide interest in understanding the genetic mechanisms behind the disease. One group of oncogenes – transcription factors – offers many opportunities for treatment or prevention. Among these transcription factors is KLF4, which functions in post-mitotic epithelial cells to promote differentiation. KLF4 has tumorigenic activity in both in vitro and in vivo models. In analyzing transcripts that were induced by KLF4, we noted the induction of multiple nuclear receptors, including retinoid receptors. Retinoids are well-established as chemopreventive agents, but the mechanisms by which they act to prevent cancer remain unclear. Previous studies have shown that KLF4 is co-expressed with the nuclear receptors RARγ and RXRα in the skin, and the formation of the skin permeability barrier is a common function of these three proteins. To examine functional interactions between KLF4 and retinoic acid receptors, we utilized a tetracycline-inducible KLF4-transgenic mouse model of cutaneous squamous cell carcinoma (SCC) together with cultured epithelial cells. Employing an RK3E epithelial cell model and multiple oncogenes (KLF4, ErbB2, Notch1, Gli1), we found that retinoids, including an RAR-selective agonist (alltrans RA), an RXR-selective agonist (9-cis UAB30, rexinoid), and a pan agonist (9-cis RA), specifically inhibit KLF4-mediated epithelial cell transformation, implicating distinct nuclear receptor heterodimers as modulators of KLF4 transforming activity. When iii iv RXRα expression was suppressed by RNAi in cultured cells, transformation was promoted and the inhibitory effect of 9cUAB30 was attenuated. Meanwhile, we also found that KLF4 rapidly induces transcripts encoding RXRα and RARγ using a conditional approach. In KLF4-transgenic mice, we found that rexinoid successfully prevented the initiation of cutaneous SCC. We further analyzed rexinoid effects in KLF4-induced epithelial cell cycling and differentiation in vivo. These studies indicate that 9cUAB30 permits KLF4 expression and cell cycling, consistent with the results of in vitro FACS analysis and cell growth assays; however, it may restrict the cell fate changes induced by KLF4, as indicated by attenuation in the misexpression of cytokeratin 1 in basal cells. Taken together, these results identify antagonism of KLF4-induced tumor initiation as a novel effect of retinoids that may contribute to their activities in cancer chemoprevention and therapy.
Recommended Citation
Jiang, Wen, "KLF4 and Retinoid Receptor Signaling in Cancer" (2009). All ETDs from UAB. 238.
https://digitalcommons.library.uab.edu/etd-collection/238