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Vol. 20, Issue 1, 419-427, January 1, 2009

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PCAF Acetylates β-Catenin and Improves Its Stability

Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and Graduate School of the Chinese Academy of Sciences, Shanghai 200031, China

Submitted August 1, 2008; Revised October 22, 2008; Accepted October 29, 2008
Monitoring Editor: Mark H. Ginsberg

β-Catenin plays an important role in development and tumorigenesis. However, the effect of a key acetyltransferase p300/CBP-associated factor (PCAF) on β-catenin signaling is largely unknown. In this study, we found PCAF could increase the β-catenin transcriptional activity, induce its nuclear translocation, and up-regulate its protein level by inhibiting its ubiquitination and improving its stability. Further studies showed that PCAF directly binds to and acetylates β-catenin. The key ubiquitination sites Lys-19 and Lys-49 of β-catenin were shown as the critical residues for PCAF-induced acetylation and stabilization. Knockdown of PCAF in colon cancer cells markedly reduced the protein level, transcriptional activity, and acetylation level of β-catenin; promoted cell differentiation; inhibited cell migration; and repressed xenografted tumorigenesis and tumor growth in nude mice. All these data demonstrate that PCAF acetylates β-catenin and regulates its stability, and they raise the prospect that therapies targeting PCAF may be of clinical use in β-catenin–driven diseases, such as colon cancer.

Address correspondence to: Qiwei Zhai (qwzhai{at}sibs.ac.cn).

Abbreviations used: CBP, CREB-binding protein; HAT, histone acetyltransferase; PCAF, p300/CBP-associated factor; RNAi, RNA interference; TCF, T cell factor; WT, wild type.

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