Transcription co-activator P300 activates Elk1-aPKC-ι signaling mediated epithelial-to-mesenchymal transition and malignancy in hepatocellular carcinoma
Transcription co-activator P300 activates Elk1-aPKC-ι signaling mediated epithelial-to-mesenchymal transition and malignancy in hepatocellular carcinoma
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DOI：
10.1038/s41389-020-0212-5
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发表时间：
2020-03-06
期刊：
影响因子：
6.2
通讯作者：
Wang, Jianming
中科院分区：
文献类型：
--
作者：
Ma, Chaoqun;Huang, Shuhong;Wang, Jianming
上皮间质转化（EMT）在肝细胞癌（HCC）的侵袭和转移中起重要作用。我们前期的研究发现非典型蛋白激酶C-iota（aPKC-iota）促进了HCC的EMT过程。然而，aPKC-1信号通路在HCC中如何调节尚未阐明。本研究利用载体转染技术研究肝癌细胞的侵袭能力，进一步阐明P300和aPKC-iota信号通路在体内外调控肝癌EMT过程中的作用机制。我们发现P300和aPKC-iota在HCC中高表达，并且它们与HCC患者的肿瘤进展和低生存率相关。P300基因敲低抑制肝癌细胞的EMT、侵袭等恶性事件，但促进细胞凋亡和周期阻滞。然而，通过P300敲低介导的作用被aPKC-1 α过表达所消除。进一步的研究表明P300通过增加aPKC-1的转录激活因子Elk 1的转录，稳定Elk 1蛋白及其磷酸化，从而上调aPKC-1的表达。总之，我们的工作揭示了致癌aPKC-iota在HCC中上调的分子机制，并表明P300与aPKC-iota一样，可用作HCC患者的预后生物标志物和治疗靶点。
Epithelial-to-mesenchymal transition (EMT) plays an important role in invasion and metastasis of hepatocellular carcinoma (HCC). Our previous study found that atypical protein kinase C-iota (aPKC-iota) promoted the EMT process in HCC. However, how the aPKC-iota signaling pathway is regulated in HCC has not been elucidated. In this study, vector transfection was utilized to study the invasion of HCC cells, and the mechanism between P300 and aPKC-iota signaling pathways in regulating the EMT process of HCC was further elucidated in vitro and in vivo. We found both P300 and aPKC-iota were highly expressed in HCC and they were correlated with tumor progression and poor survival in HCC patients. P300 knockdown inhibited EMT, invasion and other malignant events of HCC cells but promoted cell apoptosis and cycle arrest. However, the effects mediated by P300 knockdown were abolished by aPKC-iota overexpression. Further studies showed that P300 upregulates aPKC-iota expression through increasing the transcription of Elk1, a transcriptional activator of aPKC-iota, and stabilizing Elk1 protein and its phosphorylation. In conclusion, our work uncovered the molecular mechanism by which oncogenic aPKC-iota is upregulated in HCC and suggests that P300, like aPKC-iota, may be used as a prognostic biomarker and therapeutic target in patients with HCC.