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, allelc 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 p21WAF1/cip1 by KLF6 occurs through its direct recruitment to the p21WAF1/cip1 promoter and requires acelylation 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 p21WAF1/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.

Original languageEnglish
Pages (from-to)9216-9225
Number of pages10
JournalCancer Research
Volume65
Issue number20
DOIs
StatePublished - 15 Oct 2005

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