HDAC-mediated deacetylation of KLF5 associates with its proteasomal degradation.
HDAC-mediated deacetylation of KLF5 associates with its proteasomal degradation.
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DOI：
10.1016/j.bbrc.2018.04.153
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发表时间：
2018-06-07
影响因子：
3.1
通讯作者：
Dong JT
中科院分区：
文献类型：
--
作者：
Tao R;Zhang B;Li Y;King JL;Tian R;Xia S;Schiavon CR;Dong JT
KRüppel-like factor5(KLF5)是一种基本的转录因子，在肿瘤发生发展过程中调节多种细胞过程。KLF5在赖氨酸369(K369)上的乙酰化逆转了其促进细胞增殖和抑制肿瘤生长的功能。在这项研究中，我们研究了组蛋白脱乙酰酶对前列腺癌细胞株DU 145中KLF5的调节。在确认HDAC1/2在KLF5去乙酰化和促进细胞增殖中的作用的同时，我们发现，HDAC1/2的敲除上调了KLF5蛋白的表达，但不上调KLF5的mRNA表达，并且通过沉默HDAC1/2使KLF5蛋白水平升高至少部分是由于减少了蛋白酶体的降解。HDAC1/2介导的KLF5降解需要脱乙酰酶活性，KLF5突变为类似乙酰化的形式阻止其降解，即使突变不影响KLF5与HDAC1/2的结合。K369突变为精氨酸阻止乙酰化，不影响KLF5与HDAC1的结合或KLF5对HDAC1/2促进的降解的反应。这些发现提供了KLF5的乙酰化状态与其蛋白质稳定性之间的新的机制关联。他们还提出，保持KLF5的脱乙酰化状态可能是KLF5和HDAC促进细胞增殖和肿瘤生长的重要机制。
Krüppel-like factor 5 (KLF5) is a basic transcription factor that regulates diverse cellular processes during tumor development. Acetylation of KLF5 at lysine 369 (K369) reverses its function from promoting to suppressing cell proliferation and tumor growth. In this study, we examined the regulation of KLF5 by histone deacetylases in the prostate cancer cell line DU 145. While confirming the functions of HDAC1/2 in KLF5 deacetylation and the promotion of cell proliferation, we found that the knockdown of HDAC1/2 upregulated KLF5 protein but not KLF5 mRNA, and the increase in KLF5 protein level by silencing HDAC1/2 was at least in part due to decreased proteasomal degradation. Deacetylase activity was required for HDAC1/2-mediated KLF5 degradation, and mutation of KLF5 to an acetylation-mimicking form prevented its degradation, even though the mutation did not affect the binding of KLF5 with HDAC1/2. Mutation of K369 to arginine, which prevents acetylation, did not affect the binding of KLF5 to HDAC1 or the response of KLF5 to HDAC1/2-promoted degradation. These findings provide a novel mechanistic association between the acetylation status of KLF5 and its protein stability. They also suggest that maintaining KLF5 in a deacetylated form may be an important mechanism by which KLF5 and HDACs promote cell proliferation and tumor growth.
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在前列腺癌细胞中，KLF5 乙酰化的中断可将其功能从肿瘤抑制因子转变为肿瘤促进因子。
影响因子：
6.4
作者：
Li, Xin;Zhang, Baotong;Wu, Qiao;Ci, Xinpei;Zhao, Ranran;Zhang, Zhiqian;Xia, Siyuan;Su, Dan;Chen, Jie;Ma, Gui;Fu, Liya;Dong, Jin-Tang
通讯作者：
Dong, Jin-Tang
影响因子：
4.8
作者：
Chen, CS;Sun, XD;Dong, JT
通讯作者：
Dong, JT
影响因子：
4.8
作者：
Guo, Peng;Dong, Xue-Yuan;Dong, Jin-Tang
通讯作者：
Dong, Jin-Tang
影响因子：
4.8
作者：
Guo, Peng;Dong, Xue-Yuan;Dong, Jin-Tang
通讯作者：
Dong, Jin-Tang
影响因子：
4.8
作者：
Guo, Peng;Zhao, Ke-Wen;Dong, Jin-Tang
通讯作者：
Dong, Jin-Tang