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

Yaw-Dong Lang, Hsin-Yi Chen, Chun-Ming Ho, Jou-Ho Shih, En-Chi Hsu, Roger Shen, Yu-Ching Lee, Jyun-Wei Chen, Cheng-Yen Wu, Hsi-Wen Yeh, Ruey-Hwa Chen and Yuh-Shan Jou ()
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Yaw-Dong Lang: Institute of Biomedical Sciences, Academia Sinica
Hsin-Yi Chen: Graduate Institute of Cancer Biology & Drug Discovery, College of Medical Science & Technology, Taipei Medical University
Chun-Ming Ho: Institute of Biomedical Sciences, Academia Sinica
Jou-Ho Shih: Institute of Biomedical Sciences, Academia Sinica
En-Chi Hsu: Institute of Biomedical Sciences, Academia Sinica
Roger Shen: Institute of Biomedical Sciences, Academia Sinica
Yu-Ching Lee: TMU Research Center of Cancer Translational Medicine, Taipei Medical University
Jyun-Wei Chen: Institute of Biomedical Sciences, Academia Sinica
Cheng-Yen Wu: Institute of Biomedical Sciences, Academia Sinica
Hsi-Wen Yeh: Institute of Biomedical Sciences, Academia Sinica
Ruey-Hwa Chen: Institute of Biological Chemistry, Academia Sinica
Yuh-Shan Jou: Institute of Biomedical Sciences, Academia Sinica

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-13665-6

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