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KLF4 suppresses HDACi induced caspase activation and the SAPK pathway by targeting p57Kip2

Apoptosis volume 14, pages 1095–1107 (2009)Cite this article

Abstract

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.

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Acknowledgments

This work was supported by the Academic Research Fund (AcRF), Tier 1 (RG78/07), Ministry of Education, Singapore, to ZY.

Author contributions

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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Author notes

  1. Mohamed Sabry Hamza

    Present address: Schering-Plough Technologies Pte Ltd., 8 Biomedical Grove, #04-01/05, Neuros Building, Singapore, 138665, Singapore

Affiliations

  1. Division of Chemical Biology and Biotechnology, School of Biological Sciences, College of Science, Nanyang Technological University, 60 Nanyang Drive, Singapore, 637551, Singapore

    Nung Ky, Chuan Bian Lim, Jinming Li, James P. Tam & Yan Zhao

  2. Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), 60 Biopolis Street, Genome #02-01, Singapore, 138672, Singapore

    Mohamed Sabry Hamza

Authors
  1. Nung Ky
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  2. Chuan Bian Lim
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  3. Jinming Li
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  5. Mohamed Sabry Hamza
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  6. Yan Zhao
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Correspondence to Mohamed Sabry Hamza or Yan Zhao.

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Ky, N., Lim, C.B., Li, J. et al. KLF4 suppresses HDACi induced caspase activation and the SAPK pathway by targeting p57Kip2 . Apoptosis 14, 1095–1107 (2009). https://doi.org/10.1007/s10495-009-0368-0

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  • DOI: https://doi.org/10.1007/s10495-009-0368-0

Keywords

  • CDKN1C
  • HDAC
  • KLF4
  • Kruppel
  • SAHA
  • p57Kip2