YY1 and KLF4: Their Role in Gastrointestinal Malignancies

  • Himanshu Tillu
  • Ganji Purnachandra NagarajuEmail author


Gastrointestinal (GI) malignancies are among the most serious threats to global health and are among the major causes of morbidity and mortality. KLF4 and YY1 occupy a central niche and can influence the process of oncogenesis of the various tissues of the GI tract in a major way by being closely associated with several cellular processes such as cell proliferation, differentiation, DNA repair, epigenetic modifications, and apoptosis. Although evidence over the years has implicated KLF4 and YY1 in the process of tumorigenesis, significant loopholes still remain. This review is an attempt to evaluate the relative contributions of KLF4 and YY1 to various aspects of GI malignancies.


Krüppel-like factor 4 (KLF4) Yin Yang 1 (YY1) Gastric cancer (GC) Colorectal carcinoma (CRC) 


  1. 1.
    Carneiro F, Huntsman DG et al (2004) Model of the early development of diffuse GC in E-cadherin mutation carriers and its implications for patient screening. J Pathol 203(2):681–687CrossRefPubMedGoogle Scholar
  2. 2.
    Chan TA, Hermeking H, Lengauer C et al (1999) 14-3-3σ is required to prevent mitotic catastrophe after DNA damage. Nature 401(6753):616–620CrossRefPubMedGoogle Scholar
  3. 3.
    Chen HY, Lin YM, Chung HC et al (2012) miR-103/107 promote metastasis of CRC by targeting the metastasis suppressors DAPK and KLF4. Cancer Res 72(14):3631–3641CrossRefPubMedGoogle Scholar
  4. 4.
    Chen X, Johns DC, Geiman DE et al (2001) Krüppel-like factor 4 (gut-enriched Krüppel-like factor) inhibits cell proliferation by blocking G1/S progression of the cell cycle. J Biol Chem 276(32):30423–30428CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Chen ZY, Rex S et al (2004) Kruppel-like factor 4 is transactivated by butyrate in CC cells. J Nutr 134(4):792–798CrossRefPubMedGoogle Scholar
  6. 6.
    Chen ZY, Shie JL, Tseng CC (2002) Gut-enriched Krüppel-like factor represses ornithine decarboxylase gene expression and functions as checkpoint regulator in colonic cancer cells. J Biol Chem 277(48):46831–46839CrossRefPubMedGoogle Scholar
  7. 7.
    Chinnappan D, Xiao D et al (2009) Transcription factor YY1 expression in human gastrointestinal cancer cells. Int J Oncol 34(5):1417–1423PubMedGoogle Scholar
  8. 8.
    Cho YG, Song JH et al (2007) Genetic and epigenetic analysis of the KLF4 gene in GC. APMIS 115(7):802–808CrossRefPubMedGoogle Scholar
  9. 9.
    Choi BJ, Cho YG et al (2006) Altered expression of the KLF4 in CRCs. Pathol Res Pract 202(8):585–589CrossRefPubMedGoogle Scholar
  10. 10.
    Dang DT, Chen X, Feng J et al (2003) Overexpression of Krüppel-like factor 4 in the human CC cell line RKO leads to reduced tumorigenicity. Oncogene 22(22):3424–3430CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Dang DT, Bachman KE et al (2000) Decreased expression of the gut-enriched Kruppel-like factor gene in intestinal adenomas of multiple intestinal neoplasia mice and in colonic adenomas of familial adenomatous polyposis patients. FEBS Lett 476(3):203–207CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    de Nigris F, Crudele V, Giovane A et al (2010) CXCR4/YY1 inhibition impairs VEGF network and angiogenesis during malignancy. Proc Natl Acad Sci 107(32):14484–14489CrossRefPubMedGoogle Scholar
  13. 13.
    Fenoglio-Preiser CM, Wang J et al (2003) TP53 and gastric carcinoma: a review. Hum Mutat 21(3):258–270CrossRefPubMedGoogle Scholar
  14. 14.
    Garrett-Sinha LA, Eberspaecher H et al (1996) A gene for a novel zinc-finger protein expressed in differentiated epithelial cells and transiently in certain mesenchymal cells. J Biol Chem 271(49):31384–31390CrossRefPubMedGoogle Scholar
  15. 15.
    Hermeking H, Lengauer C, Polyak K et al (1997) 14-3-3σIs a p53-regulated inhibitor of G2/M progression. Mol Cell 1(1):3–11CrossRefPubMedGoogle Scholar
  16. 16.
    Jemal A, Thomas A et al (2002) Cancer statistics, 2002. CA Cancer J Clin 52(1):23–47CrossRefPubMedGoogle Scholar
  17. 17.
    Kaczynski J, Cook T et al (2003) Sp1- and Kruppel-like transcription factors. Genome Biol 4(2):206CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Kanai M, Wei D et al (2006) Loss of Kruppel-like factor 4 expression contributes to Sp1 overexpression and human GC development and progression. Clin Cancer Res 12(21):6395–6402CrossRefPubMedGoogle Scholar
  19. 19.
    Kang W, Tong JH, Lung RW et al (2015) Targeting of YAP1 by microRNA-15a and microRNA-16-1 exerts tumor suppressor function in gastric adenocarcinoma. Mol Cancer 14(1):52CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Katz JP, Perreault N et al (2005) Loss of Klf4 in mice causes altered proliferation and differentiation and precancerous changes in the adult stomach. Gastroenterology 128(4):935–945CrossRefPubMedGoogle Scholar
  21. 21.
    Kaufhold S, Garbán H et al (2016) Yin Yang 1 is associated with cancer stem cell transcription factors (SOX2, OCT4, BMI1) and clinical implication. J Exp Clin Cancer Res 35(1):84CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Kim MS, Blake M et al (2003) Inhibition of histone deacetylase increases cytotoxicity to anticancer drugs targeting DNA. Cancer Res 63(21):7291–7300PubMedGoogle Scholar
  23. 23.
    Kinzler KW, Vogelstein B (1996) Lessons from hereditary CRC. Cell 87(2):159–170CrossRefPubMedGoogle Scholar
  24. 24.
    Krstic M, Stojnev S, Jovanovic L, Marjanovic G et al (2013) KLF4 expression and apoptosis-related markers in GC. J BUON Off J Balk Union Oncol 18:695–702Google Scholar
  25. 25.
    Leng Z, Tao K, Xia Q et al (2013) Krüppel-like factor 4 acts as an oncogene in CC stem cell-enriched spheroid cells. PLoS One 8(2):e56082CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Li Q, Jia Z, Wang L et al (2012) Disruption of Klf4 in villin-positive gastric progenitor cells promotes formation and progression of tumors of the antrum in mice. Gastroenterology 142(3):531–542CrossRefPubMedGoogle Scholar
  27. 27.
    Li YL, Liu L, Xiao Y et al (2015) 14-3-3σ is an independent prognostic biomarker for GC and is associated with apoptosis and proliferation in GC. Oncol Lett 9(1):290–294CrossRefPubMedGoogle Scholar
  28. 28.
    Li Z, Dong Z, Myer D et al (2010) Role of 14-3-3σ in poor prognosis and in radiation and drug resistance of human pancreatic cancers. BMC Cancer 10(1):598CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Lin ZS, Chu HC, Yen YC et al (2012) Krüppel-like factor 4, a tumor suppressor in hepatocellular carcinoma cells reverts epithelial mesenchymal transition by suppressing slug expression. PLoS One 7(8):e43593CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Luo J, Jiang X, Cao L et al (2014) Expression of YY1 correlates with progression and metastasis in esophageal squamous cell carcinomas. Oncol Targets Ther:1753–1759Google Scholar
  31. 31.
    Luo A, Kong J et al (2004) Discovery of Ca2+−relevant and differentiation-associated genes downregulated in esophageal squamous cell carcinoma using cDNA microarray. Oncogene 23(6):1291–1299CrossRefPubMedGoogle Scholar
  32. 32.
    Neupane D, Korc M (2008) 14-3-3σ modulates pancreatic cancer cell survival and invasiveness. Clin Cancer Res 14(23):7614–7623CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Nickenig G, Baudler S, Müller et al (2002) Redox-sensitive vascular smooth muscle cell proliferation is mediated by GKLF and Id3 in vitro and in vivo. FASEB J 16(9):1077–1086CrossRefPubMedGoogle Scholar
  34. 34.
    Notarbartolo M, Giannitrapani L, Vivona N et al (2011) Frequent alteration of the yin Yang 1/Raf-1 kinase inhibitory protein ratio in hepatocellular carcinoma. Omics: J Integr Biol 15(5):267–272CrossRefGoogle Scholar
  35. 35.
    Okumura H, Kita Y, Yokomakura N et al (2010) Nuclear expression of 14-3-3 sigma is related to prognosis in patients with esophageal squamous cell carcinoma. Anticancer Res 30(12):5175–5179PubMedGoogle Scholar
  36. 36.
    Parkin DM, Bray FI et al (2001) Cancer burden in the year 2000. The global picture. Eur J Cancer 37(Suppl 8):S4–66CrossRefPubMedGoogle Scholar
  37. 37.
    Perathoner A, Pirkebner D, Brandacher G et al (2005) 14-3-3σ expression is an independent prognostic parameter for poor survival in CRC patients. Clin Cancer Res 11(9):3274–3279CrossRefPubMedGoogle Scholar
  38. 38.
    Petkova V, Romanowski MJ et al (2001) Interaction between YY1 and the Retinoblastoma Protein regulation of cell cycle progression in differentiated cells. J Biol Chem 276(11):7932–7936CrossRefPubMedGoogle Scholar
  39. 39.
    Prasad NB, Biankin AV et al (2005) Gene expression profiles in pancreatic intraepithelial neoplasia reflect the effects of Hedgehog signaling on pancreatic ductal epithelial cells. Cancer Res 65(5):1619–1626CrossRefPubMedGoogle Scholar
  40. 40.
    Preiss A, Rosenberg UB et al (1985) Molecular genetics of Kruppel, a gene required for segmentation of the Drosophila embryo. Nature 313(5997):27–32CrossRefPubMedGoogle Scholar
  41. 41.
    Roediger WE (1980) Role of anaerobic bacteria in the metabolic welfare of the colonic mucosa in man. Gut 21(9):793–798CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Saeki N, Ono H, Yanagihara K et al (2015) Rs2294008t, a risk allele for gastric and gallbladder cancers, suppresses the PSCA promoter by recruiting the transcription factor YY1. Genes Cells 20(5):382–391CrossRefPubMedGoogle Scholar
  43. 43.
    Sakamoto H, Yoshimura K, Saeki et al (2008) Genetic variation in PSCA is associated with susceptibility to diffuse-type GC. Nat Genet 40(6):730–740CrossRefPubMedGoogle Scholar
  44. 44.
    Schafer KA (1998) The cell cycle: a review. Vet Pathol 35(6):461–478CrossRefPubMedGoogle Scholar
  45. 45.
    Shi Y, Lee JS et al (1997) Everything you have ever wanted to know about Yin Yang 1. Biochim Biophys Acta 1332(2):F49–F66PubMedGoogle Scholar
  46. 46.
    Shie JL, Tseng CC (2001) A nucleus-localization-deficient mutant serves as a dominant-negative inhibitor of gut-enriched Kruppel-like factor function. Biochem Biophys Res Commun 283(1):205–208CrossRefPubMedGoogle Scholar
  47. 47.
    Shie JL, Chen ZY et al (2000) Role of gut-enriched Kruppel-like factor in colonic cell growth and differentiation. Am J Physiol Gastrointest Liver Physiol 279(4):G806–G814CrossRefPubMedGoogle Scholar
  48. 48.
    Shie JL, Chen ZY, Fu M, Pestell RG, Tseng CC (2000) Gut-enriched Krüppel-like factor represses cyclin D1 promoter activity through Sp1 motif. Nucleic Acids Res 28(15):2969–2976CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Shields JM, Christy RJ et al (1996) Identification and characterization of a gene encoding a gut-enriched Kruppel-like factor expressed during growth arrest. J Biol Chem 271(33):20009–20017CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Shrivastava A, Calame K (1994) An analysis of genes regulated by the multi-functional transcriptional regulator Yin Yang-1. Nucleic Acids Res 22(24):5151–5155CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Suske G, Bruford E et al (2005) Mammalian SP/KLF transcription factors: bring in the family. Genomics 85(5):551–556CrossRefPubMedGoogle Scholar
  52. 52.
    Tang W, Zhu Y, Gao J et al (2014) MicroRNA-29a promotes CRC metastasis by regulating matrix metalloproteinase 2 and E-cadherin via KLF4. Br J Cancer 110(2):450–458CrossRefPubMedGoogle Scholar
  53. 53.
    Tian Y, Luo A, Cai Y et al (2010) MicroRNA-10b promotes migration and invasion through KLF4 in human esophageal cancer cell lines. J Biol Chem 285(11):7986–7994CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Ton-That H, Kaestner KH et al (1997) Expression of the gut-enriched Kruppel-like factor gene during development and intestinal tumorigenesis. FEBS Lett 419(2–3):239–243CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Tsujie M, Yamamoto H et al (2000) Expression of tumor suppressor gene p16(INK4) products in primary GC. Oncology 58(2):126–136CrossRefPubMedGoogle Scholar
  56. 56.
    Wang AM, Huang TT, Hsu KW et al (2014) Yin Yang 1 is a target of microRNA-34 family and contributes to gastric carcinogenesis. Oncotarget 5(13):5002PubMedPubMedCentralGoogle Scholar
  57. 57.
    Wang FS, Liu MX et al (2002) Antitumor activities of human autologous cytokine-induced killer (CIK) cells against hepatocellular carcinoma cells in vitro and in vivo. World J Gastroenterol 8(3):464–468CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Wei D, Gong W, Kanai M, Schlunk C, Wang L, Yao JC, TT W, Huang S, Xie K (2005) Drastic down-regulation of Krüppel-like factor 4 expression is critical in human gastric cancer development and progression. Cancer Res. 65(7):2746–2754CrossRefPubMedGoogle Scholar
  59. 59.
    Wei D, Kanai M et al (2006) Emerging role of KLF4 in human gastrointestinal cancer. Carcinogenesis 27(1):23–31CrossRefPubMedGoogle Scholar
  60. 60.
    Wei D, Kanai M et al (2008) Kruppel-like factor 4 induces p27Kip1 expression in and suppresses the growth and metastasis of human pancreatic cancer cells. Cancer Res 68(12):4631–4639CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Wottrich S, Kaufhold S et al (2017) Inverse correlation between the metastasis suppressor RKIP and the metastasis inducer YY1: contrasting roles in the regulation of chemo/immuno-resistance in cancer. Drug Resist Updat 30:28–38CrossRefPubMedGoogle Scholar
  62. 62.
    Wu S, Kasim V, Kano MR et al (2013) Transcription factor YY1 contributes to tumor growth by stabilizing hypoxia factor HIF-1α in a p53-independent manner. Cancer Res 73(6):1787–1799CrossRefPubMedGoogle Scholar
  63. 63.
    Xu J, Lu B et al (2008) Dynamic down-regulation of Kruppel-like factor 4 in colorectal adenoma-carcinoma sequence. J Cancer Res Clin Oncol 134(8):891–898CrossRefPubMedGoogle Scholar
  64. 64.
    Yang Y, Goldstein BG, Chao HH, Katz J (2005) KLF4 and KLF5 regulate proliferation, apoptosis and invasion in esophageal cancer cells. Cancer Biol Ther 4(11):1216–1221CrossRefPubMedGoogle Scholar
  65. 65.
    Yin KJ, Olsen K, Hamblin M et al (2012) Vascular endothelial cell-specific microRNA-15a inhibits angiogenesis in hindlimb ischemia. J Biol Chem 287(32):27055–27064CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Yin WZ, Li F, Zhang L, Ren XP et al (2014) Down-regulation of microRNA-205 promotes GC cell proliferation. Eur Rev Med Pharmacol Sci 18(7):1027–1032PubMedGoogle Scholar
  67. 67.
    Yokoyama NN, Pate KT, Sprowl S, Waterman ML et al (2010) A role for YY1 in repression of dominant negative LEF-1 expression in CC. Nucleic Acids Res 38(19):6375–6388CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Yoon HS, Yang VW (2004) Requirement of Krüppel-like factor 4 in preventing entry into mitosis following DNA damage. J Biol Chem 279(6):5035–5041CrossRefPubMedGoogle Scholar
  69. 69.
    Yoon HS, Chen X, Yang VW (2003) Krüppel-like factor 4 mediates p53-dependent G1/S cell cycle arrest in response to DNA damage. J Biol Chem 278(4):2101–2105CrossRefPubMedGoogle Scholar
  70. 70.
    Yu T, Chen X et al (2016) KLF4 deletion alters gastric cell lineage and induces MUC2 expression. Cell Death Dis 7(6):e2255CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Zhang G, Zhu H, Wang Y et al (2009) Krüppel-like factor 4 represses transcription of the survivin gene in esophageal cancer cell lines. Biol Chem 390(5/6):463–469CrossRefPubMedGoogle Scholar
  72. 72.
    Zhang S, Jiang T, Feng L et al (2012) Yin Yang-1 suppresses differentiation of hepatocellular carcinoma cells through the downregulation of CCAAT/enhancer-binding protein alpha. J Mol Med 90(9):1069–1077CrossRefPubMedGoogle Scholar
  73. 73.
    Zhang W, Geiman DE, Shields JM et al (2000) 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 275(24):18391–18398CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Zhao W, Hisamuddin IM et al (2004) Identification of Kruppel-like factor 4 as a potential tumor suppressor gene in CRC. Oncogene 23(2):395–402CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Zheng H, Pritchard DM, Yang X et al (2009) KLF4 gene expression is inhibited by the notch signaling pathway that controls goblet cell differentiation in mouse gastrointestinal tract. Am J Physiol-Gastrointest Liver Physiol 296(3):G490–G498CrossRefPubMedGoogle Scholar
  76. 76.
    Zheng X, Li A, Zhao L et al (2013) Key role of microRNA-15a in the KLF4 suppressions of proliferation and angiogenesis in endothelial and vascular smooth muscle cells. Biochem Biophys Res Commun 437(4):625–631CrossRefPubMedGoogle Scholar
  77. 77.
    Zheng J, Liu Y, et al. (2017). miR-103 promotes proliferation and metastasis by targeting KLF4 in GC. Int J Mol Sci 18(5):910Google Scholar
  78. 78.
    Zheng L, Wang L et al (2004) Molecular basis of GC development and progression. GC 7(2):61–77Google Scholar

Copyright information

© Springer Nature Singapore Pte Ltd 2017

Authors and Affiliations

  1. 1.Sysmex India Private LimitedMumbaiIndia
  2. 2.Department of Hematology and Medical Oncology, Winship Cancer InstituteEmory UniversityAtlantaUSA

Personalised recommendations