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
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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.
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