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Prevention of KLF4-mediated tumor initiation and malignant transformation by UAB30 rexinoid
Wen Jiang1, Wentao Deng, Sarah K Bailey
1Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL, USA.
Abstract:
The transcription factor KLF4 acts in post-mitotic epithelial cells to promote differentiation and functions in a context-dependent fashion as an oncogene. In the skin KLF4 is co-expressed with the nuclear receptors RARgamma and RXRalpha, and formation of the skin permeability barrier is a shared function of these three proteins. We utilized a KLF4-transgenic mouse model of skin cancer in combination with cultured epithelial cells to examine functional interactions between KLF4 and retinoic acid receptors. In cultured cells, activation of a conditional, KLF4-estrogen receptor fusion protein by 4-hydroxytamoxifen resulted in rapid upregulation of transcripts for nuclear receptors including RARgamma and RXRalpha. We tested retinoids in epithelial cell transformation assays, including an RAR-selective agonist (all-trans RA), an RXR-selective agonist (9-cis UAB30, rexinoid), and a pan agonist (9-cis RA). Unlike for several other genes, transformation by KLF4 was inhibited by each retinoid, implicating distinct nuclear receptor heterodimers as modulators of KLF4 transforming activity. When RXRalpha expression was suppressed by RNAi in cultured cells, transformation was promoted and the inhibitory effect of 9-cis UAB30 was attenuated. Similarly as shown for other mouse models of skin cancer, rexinoid prevented skin tumor initiation resulting from induction of KLF4 in basal keratinocytes. Rexinoid permitted KLF4 expression and KLF4-induced cell cycling, but attenuated the KLF4-induced misexpression of cytokeratin 1 in basal cells. Neoplastic lesions including hyperplasia, dysplasia and squamous cell carcinoma-like lesions were prevented for up to 30 days. Taken together, the results identify retinoid receptors including RXRalpha as ligand-dependent inhibitors of KLF4-mediated transformation or tumorigenesis.
Insights
Retinoid receptors, including RXRalpha, inhibit KLF4-driven skin cancer by modulating its transforming activity. Rexinoids prevent tumor initiation and lesion development by regulating KLF4
Area of Science:
- Oncology
- Dermatology
- Molecular Biology
Background:
- The transcription factor KLF4 plays a dual role in epithelial cells, promoting differentiation but also acting as an oncogene.
- KLF4 is co-expressed with nuclear receptors RARgamma and RXRalpha in the skin, and they share functions in forming the skin permeability barrier.
- Understanding KLF4's oncogenic function and its interaction with nuclear receptors is crucial for developing targeted skin cancer therapies.
Purpose of the Study:
- To investigate the functional interactions between KLF4 and retinoic acid receptors (RARs) in skin cancer.
- To determine if retinoids can inhibit KLF4-mediated epithelial cell transformation and skin tumorigenesis.
- To elucidate the role of RXRalpha in modulating KLF4's oncogenic activity.
Main Methods:
- Utilized a KLF4-transgenic mouse model of skin cancer and cultured epithelial cells.
- Activated a conditional KLF4-estrogen receptor fusion protein and examined nuclear receptor transcript upregulation.
- Tested retinoids (RAR-selective, RXR-selective, pan agonist) in epithelial cell transformation assays.
- Investigated the effect of RXRalpha suppression via RNAi on cell transformation and retinoid response.
- Assessed the impact of rexinoid treatment on KLF4-induced skin tumor initiation and neoplastic lesion development.
Main Results:
- Retinoids, including RAR- and RXR-selective agonists, inhibited KLF4-mediated epithelial cell transformation.
- Suppression of RXRalpha promoted transformation and attenuated the inhibitory effect of the rexinoid 9-cis UAB30.
- Rexinoid treatment prevented skin tumor initiation in KLF4-transgenic mice.
- Rexinoid permitted KLF4 expression and cell cycling but reduced KLF4-induced cytokeratin 1 misexpression.
- Neoplastic lesions, including hyperplasia, dysplasia, and squamous cell carcinoma-like lesions, were prevented for up to 30 days.
Conclusions:
- Retinoid receptors, particularly RXRalpha, act as ligand-dependent inhibitors of KLF4-mediated transformation and tumorigenesis.
- Targeting retinoid receptors offers a potential therapeutic strategy for KLF4-driven skin cancers.
- KLF4's oncogenic activity is modulated by distinct nuclear receptor heterodimers, providing insights into cancer development.
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