title: KLF4 Suppresses Tumor Formation in Genetic and Pharmacological Mouse Models of Colonic Tumorigenesis.
abstract: The zinc finger transcription factor Krüppel-like factor 4 (KLF4) is frequently downregulated in colorectal cancer. Previous studies showed that KLF4 is a tumor suppressor in the intestinal tract and plays an important role in DNA damage-repair mechanisms. Here, the in vivo effects of Klf4 deletion were examined from the mouse intestinal epithelium (Klf4(ΔIS)) in a genetic or pharmacological setting of colonic tumorigenesis:Apc(Min/⁺) mutation or carcinogen treatment with azoxymethane (AOM), respectively.Klf4 (ΔIS)/Apc (Min/⁺) mice developed significantly more colonic adenomas with 100% penetrance as compared with Apc(Min/⁺) mice with intact Klf4 (Klf4(fl/fl)/Apc (Min/⁺)). The colonic epithelium of Klf4 (ΔIS)/Apc (Min/⁺)mice showed increased mTOR pathway activity, together with dysregulated epigenetic mechanism as indicated by altered expression of HDAC1 and p300. Colonic adenomas from both genotypes stained positive for γH2AX, indicating DNA double-strand breaks. InKlf4 (ΔIS)/Apc (Min/+) mice, this was associated with reduced nonhomologous end joining (NHEJ) repair and homologous recombination repair (HRR) mechanisms as indicated by reduced Ku70 and Rad51 staining, respectively. In a separate model, following treatment with AOM, Klf4 (ΔIS) mice developed significantly more colonic tumors than Klf4 (fl/fl) mice, with more Klf4 (ΔIS) mice harboring K-Rasmutations than Klf4 (fl/fl)mice. Compared with AOM-treated Klf4 (fl/fl)mice, adenomas of treated Klf4 (ΔIS) mice had suppressed NHEJ and HRR mechanisms, as indicated by reduced Ku70 and Rad51 staining. This study highlights the important role of KLF4 in suppressing the development of colonic neoplasia under different tumor-promoting conditions.
  
  
  CONCLUSIONS
  The study demonstrates that KLF4 plays a significant role in the pathogenesis of colorectal neoplasia.
authors.affiliation: Department of Medicine, Stony Brook University, Stony Brook, New York.
authors.forename: Amr M
authors.initials: AM
authors.lastname: Ghaleb
authors.affiliation: Department of Medicine, Stony Brook University, Stony Brook, New York.
authors.forename: Enas A
authors.initials: EA
authors.lastname: Elkarim
authors.affiliation: Department of Medicine, Stony Brook University, Stony Brook, New York.
authors.forename: Agnieszka B
authors.initials: AB
authors.lastname: Bialkowska
authors.affiliation: Department of Medicine, Stony Brook University, Stony Brook, New York. Department of Physiology and Biophysics, Stony Brook University, Stony Brook, New York. vincent.yang@stonybrookmedicine.edu.
authors.forename: Vincent W
authors.initials: VW
authors.lastname: Yang
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics; D000818:Animals; D001397:Azoxymethane / Q000009:adverse effects*; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000473:pathology*; D044127:Epigenesis, Genetic; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D009374:Neoplasms, Experimental; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D025601:Adenomatous Polyposis Coli Protein; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; C000613192:adenomatous polyposis coli protein, mouse; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D001397:Azoxymethane
references.citation: J Biol Chem. 1996 Aug 16;271(33):20009-17
references.pmid: 8702718
references.citation: Cell. 2004 Jan 23;116(2 Suppl):S67-9, 1 p following S69
references.pmid: 15055586
references.citation: Cancers (Basel). 2013 Jun 05;5(2):676-713
references.pmid: 24216997
references.citation: Science. 1998 Sep 4;281(5382):1509-12
references.pmid: 9727977
references.citation: Oncogene. 2004 Jan 15;23(2):395-402
references.pmid: 14724568
references.citation: Nat Genet. 2003 Dec;35(4):323-30
references.pmid: 14625550
references.citation: Science. 1993 Dec 10;262(5140):1734-7
references.pmid: 8259519
references.citation: Nat Genet. 2001 Jun;28(2):155-9
references.pmid: 11381263
references.citation: FEBS Lett. 2002 Oct 23;530(1-3):147-52
references.pmid: 12387883
references.citation: J Mol Cell Biol. 2015 Apr;7(2):132-42
references.pmid: 25801958
references.citation: Nat Genet. 2003 Jan;33(1):33-9
references.pmid: 12447373
references.citation: Cancer Res. 2007 Aug 1;67(15):7147-54
references.pmid: 17671182
references.citation: J Cell Mol Med. 2014 Jul;18(7):1460-6
references.pmid: 24779401
references.citation: Proc Natl Acad Sci U S A. 1993 Apr 1;90(7):2846-50
references.pmid: 8385345
references.citation: Nat Cell Biol. 2005 Nov;7(11):1074-82
references.pmid: 16244670
references.citation: Cell. 1997 Feb 7;88(3):323-31
references.pmid: 9039259
references.citation: Science. 1992 May 1;256(5057):668-70
references.pmid: 1350108
references.citation: Nature. 1999 Apr 1;398(6726):422-6
references.pmid: 10201372
references.citation: Cancer Res. 1994 Nov 15;54(22):5947-52
references.pmid: 7954427
references.citation: Science. 1997 Mar 21;275(5307):1787-90
references.pmid: 9065402
references.citation: J Biol Chem. 2000 Jun 16;275(24):18391-8
references.pmid: 10749849
references.citation: Nat Methods. 2012 Jul;9(7):671-5
references.pmid: 22930834
references.citation: Proc Natl Acad Sci U S A. 2000 May 9;97(10):5357-62
references.pmid: 10805796
references.citation: Oncogene. 2007 Apr 5;26(16):2365-73
references.pmid: 17016435
references.citation: Annu Rev Biochem. 2004;73:39-85
references.pmid: 15189136
references.citation: Carcinogenesis. 2000 Jun;21(6):1117-20
references.pmid: 10836998
references.citation: Nat Cell Biol. 2001 Apr;3(4):433-8
references.pmid: 11283620
references.citation: Nat Rev Mol Cell Biol. 2010 Mar;11(3):196-207
references.pmid: 20177395
references.citation: Cell. 1996 Oct 18;87(2):159-70
references.pmid: 8861899
references.citation: World J Gastroenterol. 2002 Dec;8(6):966-70
references.pmid: 12439907
references.citation: Cell Death Dis. 2014;5:e1491
references.pmid: 25341045
references.citation: Subcell Biochem. 2014;85:321-36
references.pmid: 25201202
references.citation: Oncogene. 2005 Jun 9;24(25):4017-25
references.pmid: 15806166
references.citation: Dev Biol. 2011 Jan 15;349(2):310-20
references.pmid: 21070761
references.citation: J Cell Biol. 1997 Dec 15;139(6):1553-65
references.pmid: 9396760
references.citation: Science. 1990 Jan 19;247(4940):322-4
references.pmid: 2296722
references.citation: Biochim Biophys Acta. 2012 Oct;1823(10):1666-75
references.pmid: 22766303
references.citation: Mol Cell Biol. 2006 Mar;26(6):2055-64
references.pmid: 16507986
references.citation: Mol Cancer. 2015;14:101
references.pmid: 25944097
references.citation: Science. 1997 Mar 21;275(5307):1790-2
references.pmid: 9065403
references.citation: Mol Cancer. 2013;12:89
references.pmid: 23919723
references.citation: Cancer J. 2010 Jan-Feb;16(1):39-47
references.pmid: 20164689
references.citation: Nat Cell Biol. 2001 Apr;3(4):429-32
references.pmid: 11283619
references.citation: Oncogene. 2001 Aug 9;20(35):4884-90
references.pmid: 11521200
references.citation: FEBS Lett. 2010 Sep 10;584(17):3703-8
references.pmid: 20691183
references.citation: Cancer Sci. 2004 Jun;95(6):475-80
references.pmid: 15182426
references.citation: Cell Res. 2005 Feb;15(2):92-6
references.pmid: 15740636
references.citation: J Mol Cell Biol. 2011 Feb;3(1):51-8
references.pmid: 21278452
references.citation: Cell. 1987 Feb 13;48(3):465-78
references.pmid: 2433048
references.citation: Cancer Res. 2005 Apr 1;65(7):2746-54
references.pmid: 15805274