Ge Xinjian, Jin Qihuang, Zhang Fang, Yan Tingting, Zhai Qiwei
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, China.
Mol Biol Cell. 2009 Jan;20(1):419-27. doi: 10.1091/mbc.e08-08-0792. Epub 2008 Nov 5.
beta-Catenin plays an important role in development and tumorigenesis. However, the effect of a key acetyltransferase p300/CBP-associated factor (PCAF) on beta-catenin signaling is largely unknown. In this study, we found PCAF could increase the beta-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 beta-catenin. The key ubiquitination sites Lys-19 and Lys-49 of beta-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 beta-catenin; promoted cell differentiation; inhibited cell migration; and repressed xenografted tumorigenesis and tumor growth in nude mice. All these data demonstrate that PCAF acetylates beta-catenin and regulates its stability, and they raise the prospect that therapies targeting PCAF may be of clinical use in beta-catenin-driven diseases, such as colon cancer.
β-连环蛋白在发育和肿瘤发生中起重要作用。然而，关键的乙酰转移酶p300/CBP相关因子（PCAF）对β-连环蛋白信号传导的影响在很大程度上尚不清楚。在本研究中，我们发现PCAF可增加β-连环蛋白的转录活性，诱导其核转位，并通过抑制其泛素化和提高其稳定性来上调其蛋白水平。进一步研究表明，PCAF直接结合并乙酰化β-连环蛋白。β-连环蛋白的关键泛素化位点Lys-19和Lys-49被证明是PCAF诱导的乙酰化和稳定化的关键残基。在结肠癌细胞中敲低PCAF可显著降低β-连环蛋白的蛋白水平、转录活性和乙酰化水平；促进细胞分化；抑制细胞迁移；并抑制裸鼠体内异种移植瘤的发生和肿瘤生长。所有这些数据表明PCAF使β-连环蛋白乙酰化并调节其稳定性，并且它们提出了靶向PCAF的疗法可能在β-连环蛋白驱动的疾病如结肠癌中具有临床应用前景的可能性。
