Prevention of KLF4-mediated tumor initiation and malignant transformation by UAB30 rexinoid.
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.
Jiang
Wen
W
Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL, USA.
Deng
Wentao
W
Bailey
Sarah K
SK
Nail
Clint D
CD
Frost
Andra R
AR
Brouillette
Wayne J
WJ
Muccio
Donald D
DD
Grubbs
Clinton J
CJ
Ruppert
J Michael
JM
Lobo-Ruppert
Susan M
SM
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007633:Keratins / Q000096:biosynthesis / Q000235:genetics; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D009281:Naphthalenes / Q000494:pharmacology*; D018307:Neoplasms, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051381:Rats; D018168:Receptors, Retinoic Acid / Q000819:agonists / Q000096:biosynthesis / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D047490:Retinoid X Receptor alpha / Q000819:agonists / Q000096:biosynthesis / Q000235:genetics; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D014212:Tretinoin / Q000494:pharmacology; D000097768:Retinoic Acid Receptor gamma
D000970:Antineoplastic Agents; D005231:Fatty Acids, Unsaturated; D007633:Keratins; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D009281:Naphthalenes; D018168:Receptors, Retinoic Acid; D011993:Recombinant Fusion Proteins; D047490:Retinoid X Receptor alpha; D014212:Tretinoin; D000097768:Retinoic Acid Receptor gamma; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; C000715469:Klf4 protein, rat; C112106:UAB 30