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Regulation of Kruppel-like factor 6 tumor suppressor activity by acetylation

Dan Li1, Steven Yea, Georgia Dolios

  • 1Department of Human Genetics, Mount Sinai School of Medicine, New York, NY 10029-6574, USA.

Cancer Research
|October 19, 2005
PubMed

Insights

Krüppel-like factor 6 (KLF6), a tumor suppressor, regulates cell growth by increasing p21 expression. Acetylation of KLF6 is crucial for this function, and its loss in cancer mutants impairs tumor suppression.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Epigenetics

Background:

  • Krüppel-like factor 6 (KLF6) is a tumor suppressor gene frequently inactivated in human cancers.
  • Wild-type KLF6 inhibits tumor growth partly by up-regulating p21(WAF1/cip1) (CDKN1A) in a p53-independent manner.
  • This growth-inhibitory function is often lost in tumor-derived KLF6 mutants.

Purpose of the Study:

  • To investigate the role of KLF6 acetylation in its transcriptional activity and tumor suppressive function.
  • To determine if KLF6 is directly recruited to the p21(WAF1/cip1) promoter and if its acetylation is required for transactivation.

Main Methods:

  • Chromatin immunoprecipitation (ChIP) to assess KLF6 recruitment to the p21(WAF1/cip1) promoter.
  • Mass spectrometry to detect direct lysine acetylation of KLF6 peptides.
  • Site-directed mutagenesis (K209R) to evaluate the impact of acetylation on KLF6 function.

Main Results:

  • KLF6 is directly recruited to the p21(WAF1/cip1) promoter.
  • KLF6 acetylation by histone acetyltransferases (e.g., p300/CBP) is essential for p21(WAF1/cip1) up-regulation.
  • A prostate cancer-derived KLF6 mutant (K209R) shows reduced acetylation, impaired p21(WAF1/cip1) induction, and diminished cell proliferation inhibition.

Conclusions:

  • Acetylation is a critical post-translational modification regulating KLF6 transcriptional activity.
  • Loss of KLF6 acetylation in cancer mutants contributes to its failure to suppress tumor growth, particularly in prostate cancer.

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