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KLF4 suppresses HDACi induced caspase activation and the SAPK pathway by targeting p57(Kip2)

Nung Ky1, Chuan Bian Lim, Jinming Li

  • 1Nanyang Technological University, Singapore, Singapore.

Apoptosis : an International Journal on Programmed Cell Death
|June 23, 2009
PubMed

Insights

Kruppel-like factor 4 (KLF4) unexpectedly inhibits apoptosis by blocking caspase cleavage and upregulating p57(Kip2). High KLF4 levels may cause cancer cells to resist HDAC inhibitor treatments.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Biology

Background:

  • Kruppel-like factor 4 (KLF4) is a transcription factor involved in cell differentiation and pluripotency.
  • KLF4 is highly expressed in various cancers, suggesting oncogenic and antiapoptotic roles.
  • The precise mechanisms of KLF4's function in cancer and apoptosis remain unclear.

Purpose of the Study:

  • To elucidate the role of KLF4 in apoptosis regulation, particularly during histone deacetylase inhibitor (HDACi) treatment.
  • To investigate KLF4's interaction with apoptotic pathways and its impact on cancer cell response to HDACi.

Main Methods:

  • Analysis of KLF4 induction during HDACi treatment.
  • Investigation of KLF4's effect on the extrinsic apoptosis pathway, including caspase cleavage.
  • Chromatin immunoprecipitation and reporter assays to assess KLF4 binding to the p57(Kip2) promoter.
  • Examination of KLF4's influence on the stress-activated protein kinase cascade and c-Jun phosphorylation.

Main Results:

  • KLF4 is induced by HDACi treatment and inhibits apoptosis by preventing caspase cleavage.
  • KLF4 directly binds to the p57(Kip2) promoter, leading to its transcriptional upregulation.
  • Upregulation of p57(Kip2) by KLF4 suppresses the stress-activated protein kinase cascade and c-Jun phosphorylation.
  • Cancer cells with high KLF4 expression may exhibit resistance to HDACi therapy.

Conclusions:

  • KLF4 possesses an unexpected antiapoptotic function in cancer cells.
  • KLF4 acts as a critical determinant of cell fate in response to HDACi-induced apoptosis.
  • These findings highlight KLF4's complex role in cancer and suggest therapeutic implications for HDACi treatment resistance.

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