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

Abstract

Krüppel-like factor 6 (KLF6) is a zinc finger transcription factor and tumor suppressor that is inactivated in a number of human cancers by mutation, allelic loss, and/or promoter methylation. A key mechanism of growth inhibition by wild-type KLF6 is through p53-independent up-regulation of p21(WAF1/cip1) (CDKN1A), which is abrogated in several tumor-derived mutants. Here we show by chromatin immunoprecipitation that transactivation of p21(WAF1/cip1) by KLF6 occurs through its direct recruitment to the p21(WAF1/cip1) promoter and requires acetylation by histone acetyltransferase activity of either cyclic AMP-responsive element binding protein-binding protein or p300/CBP-associated factor. Direct lysine acetylation of KLF6 peptides can be shown by mass spectrometry. A single lysine-to-arginine point mutation (K209R) derived from prostate cancer reduces acetylation of KLF6 and abrogates its capacity to up-regulate endogenous p21(WAF1/cip1) and reduce cell proliferation. These data indicate that acetylation may regulate KLF6 function, and its loss in some tumor-derived mutants could contribute to its failure to suppress growth in prostate cancer.

• Authors: Dan Li, Steven Yea, Georgia Dolios, John A Martignetti, Goutham Narla, Rong Wang, Martin J Walsh, Scott L Friedman
• Journal: Cancer research (Cancer Res) Vol. 65 Issue 20 Pg. 9216-25 (Oct 15 2005) ISSN: 0008-5472 [Print] United States
• PMID: 16230382 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• CDKN1A protein, human
• Cell Cycle Proteins
• Cyclic AMP Response Element-Binding Protein
• Cyclin-Dependent Kinase Inhibitor p21
• Histones
• KLF6 protein, human
• Kruppel-Like Factor 6
• Kruppel-Like Transcription Factors
• Proto-Oncogene Proteins
• Transcription Factors
• Histone Acetyltransferases
• p300-CBP Transcription Factors
• p300-CBP-associated factor

Topics

• Acetylation
• Amino Acid Sequence
• Animals
• Binding Sites
• Cell Cycle Proteins (metabolism)
• Cell Line, Tumor
• Chromatin Immunoprecipitation
• Cyclic AMP Response Element-Binding Protein (metabolism)
• Cyclin-Dependent Kinase Inhibitor p21 (biosynthesis, genetics)
• Histone Acetyltransferases (metabolism)
• Histones (metabolism)
• Humans
• Kruppel-Like Factor 6
• Kruppel-Like Transcription Factors (genetics, metabolism)
• Male
• Mice
• Molecular Sequence Data
• NIH 3T3 Cells
• Prostatic Neoplasms (enzymology, genetics, metabolism)
• Proto-Oncogene Proteins (genetics, metabolism)
• Transcription Factors (metabolism)
• Transcriptional Activation
• Zinc Fingers
• p300-CBP Transcription Factors