標題: | PSPC1-interchanged interactions with PTK6 and beta-catenin synergize oncogenic subcellular translocations and tumor progression |
作者: | Lang, Yaw-Dong Chen, Hsin-Yi Ho, Chun-Ming Shih, Jou-Ho Hsu, En-Chi Shen, Roger Lee, Yu-Ching Chen, Jyun-Wei Wu, Cheng-Yen Yeh, Hsi-Wen Chen, Ruey-Hwa Jou, Yuh-Shan 生物資訊及系統生物研究所 Institude of Bioinformatics and Systems Biology |
公開日期: | 16-十二月-2019 |
摘要: | Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide due to metastasis. Paraspeckle component 1 (PSPC1) upregulation has been identified as an HCC pro-metastatic activator associated with poor patient prognosis, but with a lack of targeting strategy. Here, we report that PSPC1, a nuclear substrate of PTK6, sequesters PTK6 in the nucleus and loses its metastasis driving capability. Conversely, PSPC1 upregulation or PSPC1-Y523F mutation promotes epithelial-mesenchymal transition, stemness, and metastasis via cytoplasmic translocation of active PTK6 and nuclear translocation of p-catenin, which interacts with PSPC1 to augment Wnt3a autocrine signaling. The aberrant nucleocytoplasmic shuttling of active PTK6/beta-catenin is reversed by expressing the PSPC1 C-terminal interacting domain (PSPC1-CT131), thereby suppressing PSPC1/PTK6/beta-catenin-activated metastasis to prolong the survival of HCC orthotopic mice. Thus, PSPC1 is the contextual determinant of the oncogenic switch of PTK6/beta-catenin subcellular localizations, and PSPC1-CT131 functions as a dual inhibitor of PSPC1 and PTK6 with potential for improving cancer therapy. |
URI: | http://dx.doi.org/10.1038/s41467-019-13665-6 http://hdl.handle.net/11536/153379 |
ISSN: | 2041-1723 |
DOI: | 10.1038/s41467-019-13665-6 |
期刊: | NATURE COMMUNICATIONS |
Volume: | 10 |
起始頁: | 0 |
結束頁: | 0 |
顯示於類別: | 期刊論文 |