MCC-555-induced NAG-1 expression is mediated in part by KLF4.
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.
Cekanova
Maria
M
Department of Pathobiology, College of Veterinary Medicine, The University of Tennessee, Knoxville, Tennessee 37996, USA.
Lee
Seong-Ho
SH
McEntee
Michael F
MF
Baek
Seung Joon
SJ
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
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
Oncogene. 2005 Feb 17;24(8):1412-22
15608671
Mol Cell. 1999 Jun;3(6):799-804
10394368
Nucleic Acids Res. 2000 Aug 1;28(15):2969-76
10908361
Carcinogenesis. 2002 Mar;23(3):425-34
11895857
Oncogene. 2004 Jan 15;23(2):395-402
14724568
J Biol Chem. 2003 Feb 21;278(8):5845-53
12475986
Proc Natl Acad Sci U S A. 1998 Jul 21;95(15):8806-11
9671760
Cancer Res. 2003 Mar 1;63(5):958-64
12615709
Nat Cell Biol. 2005 Nov;7(11):1074-82
16244670
Mol Pharmacol. 2001 Apr;59(4):901-8
11259636
Oncogene. 2003 May 29;22(22):3424-30
12776194
J Biol Chem. 2001 Sep 7;276(36):33384-92
11445565
Neoplasia. 2006 Oct;8(10):851-61
17032502
J Biol Chem. 2000 Jun 30;275(26):20127-35
10777512
Clin Cancer Res. 2004 Feb 15;10(4):1508-20
14977855
Mol Cancer Ther. 2006 May;5(5):1352-61
16731769
Gastroenterology. 2005 Apr;128(4):935-45
15825076
Mol Cancer Ther. 2008 Sep;7(9):2779-87
18790758
Gastroenterology. 2006 Nov;131(5):1553-60
17101328
J Pharmacol Exp Ther. 2002 Jun;301(3):1126-31
12023546
Mol Cancer Ther. 2007 May;6(5):1588-98
17513608
Mol Cancer Ther. 2008 Dec;7(12):3739-50
19074849
Cell Growth Differ. 1999 Jun;10(6):423-34
10392904
Pharmacol Res. 2007 Aug;56(2):91-8
17428674
Mol Pharmacol. 2005 Nov;68(5):1203-13
16077033
Biochem Biophys Res Commun. 2005 Mar 4;328(1):63-9
15670751
Mol Cancer Ther. 2006 Sep;5(9):2324-36
16985067
J Biol Chem. 2000 Jun 16;275(24):18391-8
10749849
Int J Cancer. 2009 Dec 15;125(12):2802-9
19551868
Pathol Res Pract. 2006;202(8):585-9
16814484
Cancer Res. 2007 Aug 1;67(15):7147-54
17671182
Int J Oncol. 2008 Apr;32(4):809-19
18360708
Cancer Res. 2000 Nov 15;60(22):6488-95
11103818
Carcinogenesis. 2007 Nov;28(11):2337-46
17724373
Cancer Res. 2005 Apr 1;65(7):2746-54
15805274