AKT-mediated regulation of chromatin ubiquitylation and tumorigenesis through Mel18 phosphorylation
AKT-mediated regulation of chromatin ubiquitylation and tumorigenesis through Mel18 phosphorylation
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AKT 通过 Mel18 磷酸化介导染色质泛素化和肿瘤发生的调节
DOI：
10.1038/s41388-020-01602-7
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发表时间：
2021-03-04
期刊：
影响因子：
8
通讯作者：
Deng，Rong
中科院分区：
文献类型：
--
作者：
Mai，Jia;Peng，Xiao-Dan;Deng，Rong
多梳阻遏复合物1（PRC 1）与基因表达和组蛋白泛素化构象的调节有关，这有助于致癌。然而，PRC 1生物发生机制的上游调控因子仍然不清楚。在这里，我们报告，polycomb组相关的哺乳动物基因Mel 18是蛋白激酶AKT的目标。AKT磷酸化T334的Mel 18，破坏Mel 18和其他PRC 1成员之间的相互作用，导致组蛋白H2 A在Lys 119的PRC 1依赖性泛素化减弱。因此，PRC 1靶基因，其中许多是已知的致癌基因，在T334-Mel 18磷酸化后被去抑制，这促进恶性行为，包括细胞增殖、肿瘤形成、迁移和侵袭、骨和脑转移性病变形成。值得注意的是，观察到AKT活性与pT 334-Mel 18之间的正相关性，并建立了基于p-AKT和pT 334-Mel 18的预测乳腺癌患者总生存期和无远处转移生存期的预后模型。这些发现对于理解AKT及其相关蛋白在染色质泛素化中的作用具有重要意义，也表明AKT-Mel 18-H2 AK 119 ub轴是癌症患者的新预后生物标志物和治疗靶点。
Polycomb repressor complex 1 (PRC1) is linked to the regulation of gene expression and histone ubiquitylation conformation, which contributes to carcinogenesis. However, the upstream regulators of PRC1 biogenesis machinery remain obscure. Here, we report that the polycomb group-related mammalian gene Mel18 is a target of the protein kinase AKT. AKT phosphorylates Mel18 at T334 to disrupt the interaction between Mel18 and other PRC1 members, leading to attenuated PRC1-dependent ubiquitylation of histone H2A at Lys119. As such, PRC1 target genes, many of which are known oncogenes, are derepressed upon T334-Mel18 phosphorylation, which promotes malignant behaviours, including cell proliferation, tumour formation, migration and invasion, bone and brain metastatic lesion formation. Notably, a positive correlation between AKT activity and pT334-Mel18 is observed, and prognostic models based on p-AKT and pT334-Mel18 that predicted overall survival and distant metastasis-free survival in breast cancer patients are established. These findings have implications for understanding the role of AKT and its associated proteins in chromatin ubiquitylation, and also indicate the AKT-Mel18-H2AK119ub axis as a novel prognostic biomarker and therapeutic target for cancer patients.