[News] 2020/01/21

Academia Sinica finds PSPC1 as a Contextual Determinant of Pro-metastatic Switch in Tumor Progression

Cancer metastasis is responsible for majority of cancer patient death. However, how cancer cells turn on the molecular metastatic switch to spread the reprogrammed cancer cells to the distant organ to cause lethality remain elusive. Therefore, targeting prognosis-related metastasis driver genes with understanding of the pathological mechanisms is critical to eliminating the metastatic signaling and prolonging the life of cancer patients. Previous reports by Dr. Yuh-Shan Jou and his lab members at the Institute of Biomedical Sciences of Academia Sinica in Taiwan identified PSPC1 (paraspeckle component 1) upregulation as the master modulator and transforming growth factor b1 (TGF-b1) pro-metastatic switch to augment cancer epithelial to mesenchymal transition (EMT), stemness and metastasis (Nature Cell Biology, 2018 and Cancer Research, 2019).

In the latest study, postdoctoral researcher Dr. Yaw-dong Lang and the collaborators found that PSPC1 is the contextual determinant to determine the subcellular localizations of nucleocytoplasmic shuttling proteins such as non-receptor protein tyrosine kinase 6 (PTK6) and β-catenin related to their tumorigenicity in human hepatocellular carcinoma (HCC). When PSPC1 is lowly expressed in the nucleus, PTK6 will interact and phosphorylate PSPC1, but be sequestered as the tumor suppressive nuclear PTK6 to diminish PSPC1 tumorigenicity. In contrast, when PSPC1 upregulation or PSPC1-Y523F mutation loses nuclear sequestration of PTK6, PTK6 will shuttle to cytoplasm to function as an oncogene, β-catenin will translocate to nucleus to interact with PSPC1 to promote Wnt3a autocrine signaling and synergize cancer EMT, stemness and metastasis. Meanwhile, we generated an antibody against phospho-Y523-PSPC1 residue and demonstrated that decreasing expression of phospho-Y523-PSPC1 residue in cancer cells indicated oncogenic activation of PSPC1/PTK6/β-catenin axis to promote tumor progression led to poor survival of HCC patients.

Moreover, the research team identified PSPC1 C-terminal interacting domain (PSPC1-CT131) as an innovative dual inhibitor to interact with PSPC1 and PTK6, to abrogate the oncogenic axis of PSPC1/PTK6/β-catenin, and to suppress tumor metastasis and  prolong the survival of HCC orthotopic mice. In summary, PSPC1 is the contextual determinant of oncogenic subcellular translocation switch to synergize tumorigenicity of PSPC1/PTK6/β-catenin axis. Detection of reducing expression of phospho-Y523-PSPC1 in cancer cells is a biomarker for the warning of tumor progression. Finally, PSPC1-CT131 is an innovative dual inhibitor of PSPC1 and PTK6 to suppress nucleocytoplasmic shuttling of oncogenes and downstream oncogenic signaling for potential improvement of cancer therapy.

This study was published online in Nature Communications the 16th December 2019. The full research article entitled “PSPC1-interchanged interactions with PTK6 and β-catenin synergize oncogenic subcellular translocations and tumor progression” is available online through the Nature Communications website at: https://www.nature.com/articles/s41467-019-13665-6. The Patent Cooperation Treaty (PCT) patent was filed for this study.

The lead author of “PSPC1-interchanged interactions with PTK6 and β-catenin synergize oncogenic subcellular translocations and tumor progression” is Dr. Yaw-Dong Lang.  Co-authors include Dr. Yuh-Shan Jou and his research team, Dr. Hsin-Yi Chen (Assistant Professor, Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University), Dr. Yu-Ching Lee (Associate Research Fellow, TMU Research Center of Cancer Translational Medicine, Taipei Medical University), and Dr. Ruey-Hwa Chen (Distinguished Research Fellow, Institute of Biological Chemistry, Academia Sinica).



(a) PTK6 suppressed PSPC1 oncogenic features by phosphorylation and interaction on Y523 of PSPC1 and was sequestered in the nucleus as a tumor suppressor. (b) PSPC1 upregulation or mutation of the PTK6 phosphorylation site PSPC1-Y523F augmented Wnt3a autocrine signaling to facilitate β-catenin nuclear and p-PTK6 cytoplasmic/membrane translocations to synergize the oncogenic signaling of both PSPC1 and PTK6, which facilitated EMT, stemness and metastasis. (c) Treatment of PSPC1-CT131 as a dual inhibitor of PSPC1 and PTK6 reduced the expression of both oncogenic PSPC1 and PTK6 to suppress HCC tumor progression.



Media Contact:
Dr. Yuh-Shan Jou, Research Fellow, Institute of Biomedical Sciences, Academia Sinica
(Tel) +886-2-2652-3521, jou@ibms.sinica.edu.tw
Dr. Yao-Dung Lang, Postdoctoral Fellow, Academia Sinica
(Tel) +886-2-2789-9062,langyd@ibms.sinica.edu.tw
Mr. Chang-Hung Chen, Secretariat Office, Central Office of Administration, Academia Sinica
(Tel) +886-2-2789-8059, changhung@gate.sinica.edu.tw
Mr. Chung-Hui Chuang, Secretariat Office, Central Office of Administration, Academia Sinica
(Tel) +886-2-2789-8820, chchuang@gate.sinica.edu.tw