The cross-talk between methylation and phosphorylation in lymphoid-specific helicase drives cancer stem-like properties.
The cross-talk between methylation and phosphorylation in lymphoid-specific helicase drives cancer stem-like properties.
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淋巴特异性解旋酶中甲基化和磷酸化之间的串扰驱动癌症干细胞样特性
DOI：
10.1038/s41392-020-00249-w
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发表时间：
2020-09-30
影响因子：
39.3
通讯作者：
Tao Y
中科院分区：
文献类型：
--
作者：
Liu N;Yang R;Shi Y;Chen L;Liu Y;Wang Z;Liu S;Ouyang L;Wang H;Lai W;Mao C;Wang M;Cheng Y;Liu S;Wang X;Zhou H;Cao Y;Xiao D;Tao Y
蛋白质的翻译后修饰(PTM)，包括染色质修饰物，在包括干细胞属性在内的各种蛋白质性质和功能的动态变化中起着至关重要的作用。然而，淋巴特异性解旋酶(LSH)，一种DNA甲基化修饰物，在调节癌症中的干状属性中的作用仍然不清楚。因此，探讨PTMS对LSH活性的调控对于进一步了解LSH的功能和活性具有重要意义。在这里，我们证明了LSH能够经历PTMS，包括甲基化和磷酸化。精氨酸甲基转移酶PRMT5可使R309残基上的LSH甲基化，同时S503残基上的MAPK1激酶也可使LSH甲基化。我们进一步表明，LSH在S503位点的磷酸化积累表现出R309残基的LSH甲基化下调，这最终促进了肺癌的干细胞样特性。然而，磷酸化缺陷的LSH S503A突变体促进了R309残基上LSH甲基化的积累，并削弱了茎状特性，表明LSH PTMS在调节茎状特性中起着关键作用。因此，我们的研究强调了LSH PTM之间的串扰在确定其在肺癌干细胞维持中的活性和功能方面的重要性。
Posttranslational modifications (PTMs) of proteins, including chromatin modifiers, play crucial roles in the dynamic alteration of various protein properties and functions including stem-cell properties. However, the roles of Lymphoid-specific helicase (LSH), a DNA methylation modifier, in modulating stem-like properties in cancer are still not clearly clarified. Therefore, exploring PTMs modulation of LSH activity will be of great significance to further understand the function and activity of LSH. Here, we demonstrate that LSH is capable to undergo PTMs, including methylation and phosphorylation. The arginine methyltransferase PRMT5 can methylate LSH at R309 residue, meanwhile, LSH could as well be phosphorylated by MAPK1 kinase at S503 residue. We further show that the accumulation of phosphorylation of LSH at S503 site exhibits downregulation of LSH methylation at R309 residue, which eventually promoting stem-like properties in lung cancer. Whereas, phosphorylation-deficient LSH S503A mutant promotes the accumulation of LSH methylation at R309 residue and attenuates stem-like properties, indicating the critical roles of LSH PTMs in modulating stem-like properties. Thus, our study highlights the importance of the crosstalk between LSH PTMs in determining its activity and function in lung cancer stem-cell maintenance.
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影响因子：
0.8
作者：
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通讯作者：
Guan, Kun-Liang
影响因子：
16.6
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Tao Y
影响因子：
12.8
作者：
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通讯作者：
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影响因子：
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作者：
Jiang Y;Mao C;Yang R;Yan B;Shi Y;Liu X;Lai W;Liu Y;Wang X;Xiao D;Zhou H;Cheng Y;Yu F;Cao Y;Liu S;Yan Q;Tao Y
通讯作者：
Tao Y