Kruppel-like factor 4 (KLF4) belongs to a family of evolutionarily conserved zinc finger-containing transcription factors. It has been shown to mediate self renewal and pluripotency, regulate adipogenesis and play a critical role in monocyte differentiation. KLF4 is also highly expressed in squamous cell carcinomas and in 70% of all primary human breast cancers, suggesting a putative role for KLF4 as being an oncogene and as an antiapoptotic factor. However, the mechanism of this regulation remains unclear. Here, we show that KLF4 is induced during histone deacetylase inhibitor treatment, and regulates the extrinsic apoptosis pathway by inhibiting caspase cleavage. In addition, KLF4 binds to the p57Kip2 promoter and transcriptionally upregulates its expression, which in turn inhibits the stress activated protein kinase cascade and c-Jun phosphorylation. Our findings indicate that in cancer cells that express high levels of KLF4 may be refractory to HDACi treatment. Results of our study demonstrate an unexpected antiapoptotic function of KLF4, and suggest an important cell fate determinant following histone deacetylase inhibitor induced apoptosis.
CDKN1C HDAC KLF4 Kruppel SAHA p57Kip2
This work was supported by the Academic Research Fund (AcRF), Tier 1 (RG78/07), Ministry of Education, Singapore, to ZY.
N.K. carried out most of the experiments; C.B.L. assisted with some experiments; M.S.H. and Z.Y. conceived and designed the project; M.S.H., N.K. and Z.Y. wrote the article. All authors participated in data analysis. All authors read and edited the article.
Conflict of interest statement
The authors declare no competing financial interests.
Martinez-Iglesias O, Ruiz-Llorente L, Sanchez-Martinez R, Garcia L, Zambrano A, Aranda A (2008) Histone deacetylase inhibitors: mechanism of action and therapeutic use in cancer. Clin Transl Oncol 10:395–398PubMedCrossRefGoogle Scholar
McLaughlin F, La Thangue NB (2004) Histone deacetylase inhibitors open new doors in cancer therapy. Biochem Pharmacol 68:1139–1144PubMedCrossRefGoogle Scholar
Di Bernardo G, Squillaro T, Dell’aversana C, et al. (2009) Histone Deacetylase inhibitors promote apoptosis and senescence in human mesenchymal stem cells. Stem Cells Dev 18(4):573–581Google Scholar
Emanuele S, Lauricella M, Tesoriere G (2008) Histone deacetylase inhibitors: apoptotic effects and clinical implications (Review). Int J Oncol 33:637–646PubMedGoogle Scholar
La Thangue NB (2004) Histone deacetylase inhibitors and cancer therapy. J Chemother 16(Suppl 4):64–67PubMedGoogle Scholar
Black AR, Black JD, Azizkhan-Clifford J (2001) Sp1 and kruppel-like factor family of transcription factors in cell growth regulation and cancer. J Cell Physiol 188:143–160PubMedCrossRefGoogle Scholar
Feinberg MW, Wara AK, Cao Z et al (2007) The Kruppel-like factor KLF4 is a critical regulator of monocyte differentiation. EMBO J 26:4138–4148PubMedCrossRefGoogle Scholar
Ghaleb AM, Nandan MO, Chanchevalap S, Dalton WB, Hisamuddin IM, Yang VW (2005) Kruppel-like factors 4 and 5: the yin and yang regulators of cellular proliferation. Cell Res 15:92–96PubMedCrossRefGoogle Scholar
Rowland BD, Bernards R, Peeper DS (2005) The KLF4 tumour suppressor is a transcriptional repressor of p53 that acts as a context-dependent oncogene. Nat Cell Biol 7:1074–1082PubMedCrossRefGoogle Scholar
Foster KW, Ren S, Louro ID et al (1999) Oncogene expression cloning by retroviral transduction of adenovirus E1A-immortalized rat kidney RK3E cells: transformation of a host with epithelial features by c-MYC and the zinc finger protein GKLF. Cell Growth Differ 10:423–434PubMedGoogle Scholar
Foster KW, Frost AR, McKie-Bell P et al (2000) Increase of GKLF messenger RNA and protein expression during progression of breast cancer. Cancer Res 60:6488–6495PubMedGoogle Scholar
Foster KW, Liu Z, Nail CD et al (2005) Induction of KLF4 in basal keratinocytes blocks the proliferation-differentiation switch and initiates squamous epithelial dysplasia. Oncogene 24:1491–1500PubMedCrossRefGoogle Scholar
Zhao Y, Hamza MS, Leong HS et al (2008) Kruppel-like factor 5 modulates p53-independent apoptosis through Pim1 survival kinase in cancer cells. Oncogene 27:1–8PubMedCrossRefGoogle Scholar
Nelson JD, Denisenko O, Bomsztyk K (2006) Protocol for the fast chromatin immunoprecipitation (ChIP) method. Nat Protoc 1:179–185PubMedCrossRefGoogle Scholar
Cucciolla V, Borriello A, Criscuolo M et al (2008) Histone deacetylase inhibitors upregulate p57Kip2 level by enhancing its expression through Sp1 transcription factor. Carcinogenesis 29:560–567PubMedCrossRefGoogle Scholar
Chang TS, Kim MJ, Ryoo K et al (2003) p57KIP2 modulates stress-activated signaling by inhibiting c-Jun NH2-terminal kinase/stress-activated protein Kinase. J Biol Chem 278:48092–48098PubMedCrossRefGoogle Scholar