title: MCC-555-induced NAG-1 expression is mediated in part by KLF4.
abstract: Peroxisome proliferator-activated receptor gamma (PPARgamma) plays a central role in cell differentiation, metabolism and tumorigenesis. We have investigated the therapeutic properties of 5-[[6-[(2-fluorophenyl)-methoxy]-2-napthalenyl]-methyl]-2,4-thiazolidinedione (MCC-555) a PPARgamma agonist in human colorectal cancer cells. To elucidate the molecular mechanism(s), by which MCC-555 exerts its effects on the human colorectal cancer cells, we have analyzed the expression of two pro-apoptotic proteins, Krüppel-like factor 4 (KLF4) and nonsteroidal anti-inflammatory drug (NSAID)-activated gene-1 (NAG-1). MCC-555-induced expression of the transcription factor, KLF-4 was blocked by a PPARgamma specific antagonist GW9662 in PPARgamma-dependent manner in HCT-116 cells. We further identified a new KLF4 target gene NAG-1, which shows a pro-apoptotic activity. We confirmed that PPARgamma agonists-induced NAG-1 expression was abolished using KLF4 siRNA in HCT-116 cells. Subsequently, KLF4 expression enhances the NAG-1 promoter activity in HCT-116 cells, and functional KLF4 binding sites in the NAG-1 promoter were also identified. MCC-555, a PPARgamma agonist induced the expression of Klf4 mRNA and protein in murine intestinal tumors from MCC-555-treated mice, as assessed by RT-PCR and immunohistochemistry. This study shows that PPARgamma agonists up-regulate KLF4 expression in receptor-dependent manner, and KLF4 was identified as a novel transcription factor that controls NAG-1 promoter activity in human and mouse colorectal cancers.
authors.affiliation: Department of Pathobiology, College of Veterinary Medicine, The University of Tennessee, Knoxville, Tennessee 37996, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Cekanova
authors.forename: Seong-Ho
authors.initials: SH
authors.lastname: Lee
authors.forename: Michael F
authors.initials: MF
authors.lastname: McEntee
authors.forename: Seung Joon
authors.initials: SJ
authors.lastname: Baek
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006131:Growth Inhibitors / Q000494:pharmacology; D045325:HCT116 Cells; D006801:Humans; D007150:Immunohistochemistry; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics*; D047495:PPAR gamma / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D045162:Thiazolidinediones / Q000494:pharmacology*; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D006131:Growth Inhibitors; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; C117339:NBAS protein, human; D009363:Neoplasm Proteins; D047495:PPAR gamma; D012333:RNA, Messenger; D045162:Thiazolidinediones; D014157:Transcription Factors; C089946:2,4-thiazolidinedione; C115174:netoglitazone
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