biostudies-literatureUnknown10(1)Lang YDHepatocellular 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.Nature communications5716https://www.ebi.ac.uk/biostudies/studies/S-EPMC6914800biostudies-literaturePSPC1-interchanged interactions with PTK6 and β-catenin synergize oncogenic subcellular translocations and tumor progression.PMC6914800Lang YDLee YCJou YSHsu ECChen RHChen JWWu CYChen HYHo CMShen RYeh HWShih JHfalsePSPC1-interchanged interactions with PTK6 and β-catenin synergize oncogenic subcellular translocations and tumor progression.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.2019-01-01T00:00:00Z2019 Dec2026-04-30T15:55:54.665Z2020-05-22T00:03:49ZS-EPMC69148003184405710.1038/s41467-019-13665-6