PSPC1-interchanged interactions with PTK6 and β-catenin synergize oncogenic subcellular translocations and tumor progression

• Published in: Nature communications Vol. 10; no. 1; pp. 5716 - 16
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16.12.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/1; 13/105; 13/44; 13/51; 14/19; 38/91; 59/5; 631/67/1504/1610/4029; 631/67/322; 64/60; 82/58; Adult; Aged; Animals; beta Catenin - metabolism; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - mortality; Carcinoma, Hepatocellular - pathology; Cell Line, Tumor; Cell Nucleus - metabolism; Cytoplasm - metabolism; Disease Progression; Epithelial-Mesenchymal Transition - genetics; Female; Hepatocellular carcinoma; Humanities and Social Sciences; Humans; Kaplan-Meier Estimate; Liver - pathology; Liver cancer; Liver Neoplasms - genetics; Liver Neoplasms - mortality; Liver Neoplasms - pathology; Male; Metastases; Metastasis; Mice; Middle Aged; multidisciplinary; Mutation; Neoplasm Proteins - metabolism; Protein-Tyrosine Kinases - metabolism; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Science; Science (multidisciplinary); Signal Transduction; Synergism; Translocation; Up-Regulation; Wnt3A Protein - metabolism; Xenograft Model Antitumor Assays; Young Adult; β-Catenin
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-13665-6

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 β-catenin, which interacts with PSPC1 to augment Wnt3a autocrine signaling. The aberrant nucleocytoplasmic shuttling of active PTK6/β-catenin is reversed by expressing the PSPC1 C-terminal interacting domain (PSPC1-CT131), thereby suppressing PSPC1/PTK6/β-catenin-activated metastasis to prolong the survival of HCC orthotopic mice. Thus, PSPC1 is the contextual determinant of the oncogenic switch of PTK6/β-catenin subcellular localizations, and PSPC1-CT131 functions as a dual inhibitor of PSPC1 and PTK6 with potential for improving cancer therapy. PSPC1 has a critical role in promoting EMT and metastasis. Here, the authors demonstrate that PSPC1 is the contextual determinant of the oncogenic switch of PTK6/β-catenin subcellular localizations to drive metastasis of hepatocellular carcinoma cells via a PSPC1/PTK6/β-catenin signaling.