Interruption of KLF5 acetylation converts its function from tumor suppressor to tumor promoter in prostate cancer cells.
Interruption of KLF5 acetylation converts its function from tumor suppressor to tumor promoter in prostate cancer cells.
复制标题
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。
DOI：
10.1002/ijc.29028
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发表时间：
2015-02-01
影响因子：
6.4
通讯作者：
Dong, Jin-Tang
中科院分区：
文献类型：
--
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
KLF5同时具有抑瘤和促瘤作用，但其作用机制尚不清楚。在培养的非癌上皮细胞中，KLF5在转化生长因子β诱导的乙酰化作用下从促增殖活性转变为抗增殖活性，从而改变KLF5转录复合体和p15、myc等基因的表达。在这项研究中，我们利用转化生长因子β抑制增殖的PC-3和DU145前列腺癌细胞株，检测KLF5的乙酰化状态是否也决定了其在肿瘤发生中的相反功能。KLF5对癌细胞的增殖有抑制作用，其抑制作用依赖于KLF5的乙酰化。MYC和p15表现出与非癌细胞相同的表达变化模式。在裸鼠体内，KLF5也以乙酰化依赖的方式抑制肿瘤生长。此外，去乙酰化使KLF5具有促肿瘤活性，阻断转化生长因子β信号转导减弱了KLF5的抑瘤活性。RNA-Seq和综合数据分析表明，包括RelA、P53、CREB1、MYC、JUN、ER、AR和SP1在内的多个分子介导了AcKLF5和unAcKLF5的相反功能。这些结果为KLF5从抗肿瘤功能转换为促肿瘤功能的机制提供了新的见解，并提示了AcKLF5和unAcKLF5分别在转化生长因子β的肿瘤抑制和促肿瘤功能中的作用。
KLF5 possesses both tumor suppressing and tumor promoting activities, though the mechanism controlling these opposing functions is unknown. In cultured non-cancerous epithelial cells, KLF5 converts from pro-proliferative to anti-proliferative activity upon TGFβ-induced acetylation, which sequentially alters the KLF5 transcriptional complex and the expression of genes such as p15 and MYC. In this study, we tested whether the acetylation status of KLF5 also determines its opposing functions in tumorigenesis using the PC-3 and DU 145 prostate cancer cell lines, whose proliferation is inhibited by TGFβ. KLF5 inhibited the proliferation of these cancer cells, and the inhibition was dependent on KLF5 acetylation. MYC and p15 showed the same patterns of expression change found in non-cancerous cells. In nude mice, KLF5 also suppressed tumor growth in an acetylation-dependent manner. Furthermore, deacetylation switched KLF5 to tumor promoting activity, and blocking TGFβ signaling attenuated the tumor suppressor activity of KLF5. RNA-Seq and comprehensive data analysis suggest that multiple molecules, including RELA, p53, CREB1, MYC, JUN, ER, AR and SP1, mediate the opposing functions of AcKLF5 and unAcKLF5. These results provide novel insights into the mechanism by which KLF5 switches from anti-tumorigenic to pro-tumorigenic function, and also suggest the roles of AcKLF5 and unAcKLF5, respectively, in the tumor suppressing and tumor promoting functions of TGFβ.
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影响因子：
11.2
作者：
McConnell BB;Bialkowska AB;Nandan MO;Ghaleb AM;Gordon FJ;Yang VW
通讯作者：
Yang VW
影响因子：
6.4
作者：
Guo, Peng;Dong, Xue-Yuan;Zhao, Ke-Wen;Sun, Xiaodong;Li, Qunna;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;Dong, Xue-Yuan;Dong, Jin-Tang
通讯作者：
Dong, Jin-Tang
影响因子：
21.3
作者：
Jiang, Jianming;Chan, Yun-Shen;Ng, Huck-Hui
通讯作者：
Ng, Huck-Hui