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Regulation of Krüppel-like Factor 6 Tumor Suppressor Activity by Acetylation

¹ Division of Liver Diseases, Department of Medicine; and Departments of ² Human Genetics and ³ Pediatrics, Mount Sinai School of Medicine, New York, New York

Requests for reprints: Scott L. Friedman, Mount Sinai School of Medicine, Box 1123, 1425 Madison Avenue, Room 11-70C, New York, NY 10029-6574. Phone: 212-659-9501; Fax: 212-849-2574; E-mail: Scott.Friedman{at}mssm.edu.

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.

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