Skip to main content

Advertisement

SpringerLink
Log in

The pathobiology of Krüppel-like factors in colorectal cancer

  • Published:
Current Colorectal Cancer Reports

Abstract

The Krüppel-like factor (KLF) proteins are zinc finger-containing transcription factors that exert important functions in regulating diverse biologic processes such as growth, proliferation, differentiation, development, inflammation, and apoptosis. Many KLFs have also been shown to play significant roles in tumorigenesis of various organs and tissues. Three in particular—KLF4, KLF5, and KLF6—are often dysregulated in tumors of the gastrointestinal tract, including colorectal cancer. This article reviews the functions of these three KLFs in normal gastrointestinal biology and their pathobiologic roles in colorectal cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. American Cancer Society: Cancer Facts & Figures 2007. Atlanta: American Cancer Society; 2007. Available at http://www.cancer.org/downloads/STT/CAFF2007PWSecured.pdf. Accessed December 7, 2007.

    Google Scholar 

  2. Hisamuddin IM, Yang VW: Molecular genetics of colorectal cancer: An overview. Curr Colorectal Cancer Rep 2006, 2:53–59.

    Article  PubMed  Google Scholar 

  3. Muto T, Bussey HJ, Morson BC: The evolution of cancer of the colon and rectum. Cancer 1975, 36:2251–2270.

    Article  PubMed  CAS  Google Scholar 

  4. Fearon ER, Vogelstein B: A genetic model for colorectal tumorigenesis. Cell 1990, 61:759–767.

    Article  PubMed  CAS  Google Scholar 

  5. Wood LD, Parsons DW, Jones S, et al.: The genomic landscapes of human breast and colorectal cancers. Science 2007, 318:1108–1113.

    Article  PubMed  CAS  Google Scholar 

  6. Vogelstein B, Kinzler KW: Cancer genes and the pathways they control. Nat Med 2004, 10:789–799.

    Article  PubMed  CAS  Google Scholar 

  7. Schuh R, Aicher W, Gaul U, et al.: A conserved family of nuclear proteins containing structural elements of the finger protein encoded by Krüppel, a Drosophila segmentation gene. Cell 1986, 47:1025–1032.

    Article  PubMed  CAS  Google Scholar 

  8. Bieker JJ: Krüppel-like factors: three fingers in many pies. J Biol Chem 2001, 276:34355–34358.

    Article  PubMed  CAS  Google Scholar 

  9. Black AR, Black JD, Azizkhan-Clifford J: Sp1 and Krüppellike factor family of transcription factors in cell growth regulation and cancer. J Cell Physiol 2001, 188:143–160.

    Article  PubMed  CAS  Google Scholar 

  10. Dang DT, Pevsner J, Yang VW: The biology of the mammalian Krüppel-like family of transcription factors. Int J Biochem Cell Biol 2000, 32:1103–1121.

    Article  PubMed  CAS  Google Scholar 

  11. Kaczynski J, Cook T, Urrutia R: Sp1-and Krüppel-like transcription factors. Genome Biol 2003, 4:206.

    Article  PubMed  Google Scholar 

  12. Ghaleb AM, Nandan MO, Chanchevalap S, et al.: Krüppel-like factors 4 and 5: the yin and yang regulators of cellular proliferation. Cell Res 2005, 15:92–96.

    Article  PubMed  CAS  Google Scholar 

  13. McConnell BB, Ghaleb AM, Nandan MO, Yang VW: The diverse functions of Krüppel-like factors 4 and 5 in epithelial biology and pathobiology. Bioessays 2007, 29:549–557.

    Article  PubMed  CAS  Google Scholar 

  14. Narla G, Friedman SL, Martignetti JA: Krüppel cripples prostate cancer: KLF6 progress and prospects. Am J Pathol 2003, 162:1047–1052.

    PubMed  Google Scholar 

  15. Wang X, Zhao J: KLF8 transcription factor participates in oncogenic transformation. Oncogene 2007, 26:456–461.

    Article  PubMed  CAS  Google Scholar 

  16. Ellenrieder V, Buck A, Harth A, et al.: KLF11 mediates a critical mechanism in TGF-beta signaling that is inactivated by Erk-MAPK in pancreatic cancer cells. Gastroenterology 2004, 127:607–620.

    Article  PubMed  CAS  Google Scholar 

  17. Shields JM, Christy RJ, Yang VW: Identification and characterization of a gene encoding a gut-enriched Krüppel-like factor expressed during growth arrest. J Biol Chem 1996, 271:20009–20017.

    Article  PubMed  CAS  Google Scholar 

  18. Shields JM, Yang VW: Two potent nuclear localization signals in the gut-enriched Krüppel-like factor define a subfamily of closely related Krüppel proteins. J Biol Chem 1997, 272:18504–18507.

    Article  PubMed  CAS  Google Scholar 

  19. Shields JM, Yang VW: Identification of the DNA sequence that interacts with the gut-enriched Krüppel-like factor. Nucleic Acids Res 1998, 26:796–802.

    Article  PubMed  CAS  Google Scholar 

  20. Zhang W, Shields JM, Sogawa K, et al.: The gut-enriched Krüppel-like factor suppresses the activity of the CYP1A1 promoter in an Sp1-dependent fashion. J Biol Chem 1998, 273:17917–17925.

    Article  PubMed  CAS  Google Scholar 

  21. Ton-That H, Kaestner KH, Shields JM, et al.: Expression of the gut-enriched Krüppel-like factor gene during development and intestinal tumorigenesis. FEBS Lett 1997, 419:239–243.

    Article  PubMed  CAS  Google Scholar 

  22. Chen X, Johns DC, Geiman DE, et al.: Krüppel-like factor 4 (gut-enriched Krüppel-like factor) inhibits cell proliferation by blocking G1/S progression of the cell cycle. J Biol Chem 2001, 276:30423–30428.

    Article  PubMed  CAS  Google Scholar 

  23. Yoon HS, Chen X, Yang VW: Krüppel-like factor 4 mediates p53-dependent G1/S cell cycle arrest in response to DNA damage. J Biol Chem 2003, 278:2101–2105.

    Article  PubMed  CAS  Google Scholar 

  24. Yoon HS, Yang VW: Requirement of Krüppel-like factor 4 in preventing entry into mitosis following DNA damage. J Biol Chem 2004, 279:5035–5041.

    Article  PubMed  CAS  Google Scholar 

  25. Zhang W, Geiman DE, Shields JM, et al.: The gut-enriched Krüppel-like factor (Krüppel-like factor 4) mediates the transactivating effect of p53 on the p21 WAF1/CIP1 promoter. J Biol Chem 2000, 275:18391–18398.

    Article  PubMed  CAS  Google Scholar 

  26. Chen X, Whitney EM, Gao SY, Yang VW: Transcriptional profiling of Krüppel-like factor 4 reveals a function in cell cycle regulation and epithelial differentiation. J Mol Biol 2003, 326:665–677.

    Article  PubMed  CAS  Google Scholar 

  27. Dang DT, Bachman KE, Mahatan CS, et al.: Decreased expression of the gut-enriched Krüppel-like factor gene in intestinal adenomas of multiple intestinal neoplasia mice and in colonic adenomas of familial adenomatous polyposis patients. FEBS Lett 2000, 476:203–207.

    Article  PubMed  CAS  Google Scholar 

  28. Dang DT, Chen X, Feng J, et al.: Overexpression of Krüppel-like factor 4 in the human colon cancer cell line RKO leads to reduced tumorigenecity. Oncogene 2003, 22:3424–3430.

    Article  PubMed  CAS  Google Scholar 

  29. Dang DT, Mahatan CS, Dang LH, et al.: Expression of the gut-enriched Krüppel-like factor (Krüppel-like factor 4) gene in the human colon cancer cell line RKO is dependent on CDX2. Oncogene 2001, 20:4884–4890.

    Article  PubMed  CAS  Google Scholar 

  30. Clevers H: Wnt/beta-catenin signaling in development and disease. Cell 2006, 127:469–480.

    Article  PubMed  CAS  Google Scholar 

  31. Stone CD, Chen ZY, Tseng CC: Gut-enriched Krüppel-like factor regulates colonic cell growth through APC/beta-catenin pathway. FEBS Lett 2002, 530:147–152.

    Article  PubMed  CAS  Google Scholar 

  32. Zhang W, Chen X, Kato Y, et al.: Novel cross talk of Krüppel-like factor 4 and beta-catenin regulates normal intestinal homeostasis and tumor repression. Mol Cell Biol 2006, 26:2055–2064.

    Article  PubMed  CAS  Google Scholar 

  33. Ghaleb AM, McConnell BB, Nandan MO, et al.: Haploinsufficiency of Krüppel-like factor 4 promotes adenomatous polyposis coli dependent intestinal tumorigenesis. Cancer Res 2007, 67:7147–7154.

    Article  PubMed  CAS  Google Scholar 

  34. Moser AR, Pitot HC, Dove WF: A dominant mutation that predisposes to multiple intestinal neoplasia in the mouse. Science 1990, 247:322–324.

    Article  PubMed  CAS  Google Scholar 

  35. Shie JL, Chen ZY, O’Brien MJ, et al.: Role of gut-enriched Krüppel-like factor in colonic cell growth and differentiation. Am J Physiol Gastrointest Liver Physiol 2000, 279:G806–G814.

    PubMed  CAS  Google Scholar 

  36. Zhao W, Hisamuddin IM, Nandan MO, et al.: Identification of Krüppel-like factor 4 as a potential tumor suppressor gene in colorectal cancer. Oncogene 2004, 23:395–402.

    Article  PubMed  CAS  Google Scholar 

  37. Yoon HS, Ghaleb AM, Nandan MO, et al.: Krüppel-like factor 4 prevents centrosome amplification following gamma-irradiation-induced DNA damage. Oncogene 2005, 24:4017–4025.

    PubMed  CAS  Google Scholar 

  38. Katz JP, Perreault N, Goldstein BG, et al.: The zinc-finger transcription factor K1f4 is required for terminal differentiation of goblet cells in the colon. Development 2002, 129:2619–2628.

    PubMed  CAS  Google Scholar 

  39. van Es JH, van Gijn ME, Riccio O, et al.: Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature 2005, 435:959–963.

    Article  PubMed  CAS  Google Scholar 

  40. de Lau W, Barker N, Clevers H: WNT signaling in the normal intestine and colorectal cancer. Front Biosci 2007, 12:471–491.

    Article  PubMed  Google Scholar 

  41. Conkright MD, Wani MA, Anderson KP, Lingrel JB: A gene encoding an intestinal-enriched member of the Krüppel-like factor family expressed in intestinal epithelial cells. Nucleic Acids Res 1999, 27:1263–1270.

    Article  PubMed  CAS  Google Scholar 

  42. Sogawa K, Imataka H, Yamasaki Y, et al.: cDNA cloning and transcriptional properties of a novel GC box-binding protein, BTEB2. Nucleic Acids Res 1993, 21:1527–1532.

    Article  PubMed  CAS  Google Scholar 

  43. Ohnishi S, Laub F, Matsumoto N, et al.: Developmental expression of the mouse gene coding for the Krüppel-like transcription factor KLF5. Dev Dyn 2000, 217:421–429.

    Article  PubMed  CAS  Google Scholar 

  44. Shindo T, Manabe I, Fukushima Y, et al.: Krüppel-like zinc-finger transcription factor KLF5/BTEB2 is a target for angiotensin II signaling and an essential regulator of cardiovascular remodeling. Nat Med 2002, 8:856–863.

    PubMed  CAS  Google Scholar 

  45. Sun R, Chen X, Yang VW: Intestinal-enriched Krüppel-like factor (Krüppel-like factor 5) is a positive regulator of cellular proliferation. J Biol Chem 2001, 276:6897–6900.

    Article  PubMed  CAS  Google Scholar 

  46. Chanchevalap S, Nandan MO, Merlin D, Yang VW: All- trans retinoic acid inhibits proliferation of intestinal epithelial cells by inhibiting expression of the gene encoding Krüppel-like factor 5. FEBS Lett 2004, 578:99–105.

    Article  PubMed  CAS  Google Scholar 

  47. Zhang H, Bialkowska A, Rusovici R, et al.: Lysophosphatidic acid facilitates proliferation of colon cancer cells via induction of Krüppel-like factor 5. J Biol Chem 2007, 282:15541–15549.

    Article  PubMed  CAS  Google Scholar 

  48. Ziemer LT, Pennica D, Levine AJ: Identification of a mouse homolog of the human BTEB2 transcription factor as a β-catenin-independent Wnt-1-responsive gene. Mol Cell Biol 2001, 21:562–574.

    Article  PubMed  CAS  Google Scholar 

  49. Chen C, Bhalala HV, Qiao H, Dong JT: A possible tumor suppressor role of the KLF5 transcription factor in human breast cancer. Oncogene 2002, 21:6567–6572.

    Article  PubMed  CAS  Google Scholar 

  50. Chen C, Bhalala HV, Vessella RL, Dong JT: KLF5 is frequently deleted and down-regulated but rarely mutated in prostate cancer. Prostate 2003, 55:81–88.

    Article  PubMed  CAS  Google Scholar 

  51. Nandan MO, Chanchevalap S, Dalton WB, Yang VW: Krüppel-like factor 5 promotes mitosis by activating the cyclin B1/Cdc2 complex during oncogenic Ras-mediated transformation. FEBS Lett 2005, 579:4757–4762.

    Article  PubMed  CAS  Google Scholar 

  52. Nandan MO, Yoon HS, Zhao W, et al.: Krüppel-like factor 5 mediates the transforming activity of oncogenic H-Ras. Oncogene 2004, 23:3404–3413.

    Article  PubMed  CAS  Google Scholar 

  53. Du JX, Yun CC, Bialkowska A, Yang VW: Protein inhibitor of activated STAT1 interacts with and up-regulates activities of the pro-proliferative transcription factor Krüppel-like factor 5. J Biol Chem 2007, 282:4782–4793.

    Article  PubMed  CAS  Google Scholar 

  54. Bateman NW, Tan D, Pestell RG, et al.: Intestinal tumor progression is associated with altered function of KLF5. J Biol Chem 2004, 279:12093–12101.

    Article  PubMed  CAS  Google Scholar 

  55. Nandan MO, McConnell BB, Ghaleb AM, et al.: Krüppel-like factor 5 mediates cellular transformation during oncogenic KRAS -induced intestinal tumorigenesis. Gastroenterology 2008, 134:120–130.

    Article  PubMed  CAS  Google Scholar 

  56. Bos JL, Fearon ER, Hamilton SR, et al.: Prevalence of ras gene mutations in human colorectal cancers. Nature 1987, 327:293–297.

    Article  PubMed  CAS  Google Scholar 

  57. Koritschoner NP, Bocco JL, Panzetta-Dutari GM, et al.: A novel human zinc finger protein that interacts with the core promoter element of a TATA box-less gene. J Biol Chem 1997, 272:9573–9580.

    Article  PubMed  CAS  Google Scholar 

  58. Okano J, Opitz OG, Nakagawa H, et al.: The Krüppel-like transcriptional factors Zf9 and GKLF coactivate the human keratin 4 promoter and physically interact. FEBS Lett 2000, 473:95–100.

    Article  PubMed  CAS  Google Scholar 

  59. Narla G, Heath KE, Reeves HL, et al.: KLF6, a candidate tumor suppressor gene mutated in prostate cancer. Science 2001, 294:2563–2566.

    Article  PubMed  CAS  Google Scholar 

  60. Benzeno S, Narla G, Allina J, et al.: Cyclin-dependent kinase inhibition by the KLF6 tumor suppressor protein through interaction with cyclin D1. Cancer Res 2004, 64:3885–3891.

    Article  PubMed  CAS  Google Scholar 

  61. Kremer-Tal S, Reeves HL, Narla G, et al.: Frequent inactivation of the tumor suppressor Krüppel-like factor 6 (KLF6) in hepatocellular carcinoma. Hepatology 2004, 40:1047–1052.

    Article  PubMed  CAS  Google Scholar 

  62. Cho YG, Kim CJ, Park CH, et al.: Genetic alterations of the KLF6 gene in gastric cancer. Oncogene 2005, 24:4588–4590.

    Article  PubMed  CAS  Google Scholar 

  63. Reeves HL, Narla G, Ogunbiyi O, et al.: Krüppel-like factor 6 (KLF6) is a tumor-suppressor gene frequently inactivated in colorectal cancer. Gastroenterology 2004, 126:1090–1103.

    Article  PubMed  CAS  Google Scholar 

  64. Cho YG, Choi BJ, Kim CJ, et al.: Genetic alterations of the KLF6 gene in colorectal cancers. APMIS 2006, 114:458–464.

    Article  PubMed  CAS  Google Scholar 

  65. Cho YG, Choi BJ, Song JW, et al.: Aberrant expression of Krüppel-like factor 6 protein in colorectal cancers. World J Gastroenterol 2006, 12:2250–2253.

    PubMed  CAS  Google Scholar 

  66. Mukai S, Hiyama T, Tanaka S, et al.: Involvement of Krüppel-like factor 6 (KLF6) mutation in the development of nonpolypoid colorectal carcinoma. World J Gastroenterol 2007, 13:3932–3938.

    PubMed  CAS  Google Scholar 

  67. Miyaki M, Yamaguchi T, Iijima T, et al.: Difference in the role of loss of heterozygosity at 10p15 (KLF6 locus) in colorectal carcinogenesis between sporadic and familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer patients. Oncology 2006, 71:131–135.

    Article  PubMed  CAS  Google Scholar 

  68. Lievre A, Landi B, Cote JF, et al.: Absence of mutation in the putative tumor-suppressor gene KLF6 in colorectal cancers. Oncogene 2005, 24:7253–7256.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Digestive Diseases, Department of Medicine, Emory, University School of Medicine, 201 Whitehead Biomedical Research Building, 615 Michael Street, Atlanta, GA, 30322, USA

    Vincent W. Yang

Authors
  1. Amr M. Ghaleb
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vincent W. Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Vincent W. Yang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ghaleb, A.M., Yang, V.W. The pathobiology of Krüppel-like factors in colorectal cancer. Curr colorectal cancer rep 4, 59–64 (2008). https://doi.org/10.1007/s11888-008-0011-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11888-008-0011-4

Keywords

Search

Navigation