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Phosphorylated PTTG1 switches its subcellular distribution and promotes β-catenin stabilization and subsequent transcription activity

Oncogene volume 42, pages 2439–2455 (2023)Cite this article

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Abstract

The Wnt/β-catenin signaling is usually abnormally activated in hepatocellular carcinoma (HCC), and pituitary tumor-transforming gene 1 (PTTG1) has been found to be highly expressed in HCC. However, the specific mechanism of PTTG1 pathogenesis remains poorly understood. Here, we found that PTTG1 is a bona fide β-catenin binding protein. PTTG1 positively regulates Wnt/β-catenin signaling by inhibiting the destruction complex assembly, promoting β-catenin stabilization and subsequent nuclear localization. Moreover, the subcellular distribution of PTTG1 was regulated by its phosphorylation status. Among them, PP2A induced PTTG1 dephosphorylation at Ser165/171 residues and prevented PTTG1 translocation into the nucleus, but these effects were effectively reversed by PP2A inhibitor okadaic acid (OA). Interestingly, we found that PTTG1 decreased Ser9 phosphorylation-inactivation of GSK3β by competitively binding to PP2A with GSK3β, indirectly leading to cytoplasmic β-catenin stabilization. Finally, PTTG1 was highly expressed in HCC and associated with poor patient prognosis. PTTG1 could promote the proliferative and metastasis of HCC cells. Overall, our results indicated that PTTG1 plays a crucial role in stabilizing β-catenin and facilitating its nuclear accumulation, leading to aberrant activation of Wnt/β-catenin signaling and providing a feasible therapeutic target for human HCC.

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Fig. 1: PTTG1 positively regulates Wnt signaling by promoting β-catenin nuclear localization and target genes transcription in HCC cells.
Fig. 2: PTTG1 is a novel member of the β-catenin destruction complex.
Fig. 3: Domain mapping of PTTG1-β-catenin and PTTG1-GSK3β interaction.
Fig. 4: PTTG1 inhibits β-catenin destruction complex assembly and promotes stabilization of β-catenin.
Fig. 5: PP2A mediated PTTG1 dephosphorylation at Ser165 and Ser171.
Fig. 6: PP2A inhibits PTTG1 nuclear accumulation and its nucleocytoplasmic distribution is dependent on the phosphorylation status of PTTG1.
Fig. 7: PP2A preferentially dephosphorylates PPTG1 to prevent GSK3β dephosphorylation.
Fig. 8: PTTG1 promotes the proliferation and metastasis of HCC cells.
Fig. 9: PTTG1 is up-regulated in HCC patients.

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Data availability

Please contact the corresponding author (Jingfeng_hut@163.com or cefan@hbut.edu.cn) for data requests.

References

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–49.

    Article  PubMed  Google Scholar 

  2. Papatheodoridi A, Papatheodoridis G Hepatocellular carcinoma: the virus or the liver? Liver Int. 2022. Online ahead of print.

  3. Raoul JL, Frenel JS, Raimbourg J, Gilabert M. Current options and future possibilities for the systemic treatment of hepatocellular carcinoma. Hepat Oncol. 2019;6:Hep11.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Cheng H, Sun G, Chen H, Li Y, Han Z, Li Y, et al. Trends in the treatment of advanced hepatocellular carcinoma: immune checkpoint blockade immunotherapy and related combination therapies. Am J Cancer Res. 2019;9:1536–45.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Perugorria MJ, Olaizola P, Labiano I, Esparza-Baquer A, Marzioni M, Marin JJG, et al. Wnt-β-catenin signalling in liver development, health and disease. Nat Rev Gastroenterol Hepatol. 2019;16:121–36.

    Article  CAS  PubMed  Google Scholar 

  6. Rubinfeld B, Albert I, Porfiri E, Fiol C, Munemitsu S, Polakis P. Binding of GSK3beta to the APC-beta-catenin complex and regulation of complex assembly. Science. 1996;272:1023–6.

    Article  CAS  PubMed  Google Scholar 

  7. Latres E, Chiaur DS, Pagano M. The human F box protein beta-Trcp associates with the Cul1/Skp1 complex and regulates the stability of beta-catenin. Oncogene. 1999;18:849–54.

    Article  CAS  PubMed  Google Scholar 

  8. Clevers H. Wnt/beta-catenin signaling in development and disease. Cell. 2006;127:469–80.

    Article  CAS  PubMed  Google Scholar 

  9. Kim W, Kim M, Jho EH. Wnt/β-catenin signalling: from plasma membrane to nucleus. Biochem J. 2013;450:9–21.

    Article  CAS  PubMed  Google Scholar 

  10. Pei L, Melmed S. Isolation and characterization of a pituitary tumor-transforming gene (PTTG). Mol Endocrinol. 1997;11:433–41.

    Article  CAS  PubMed  Google Scholar 

  11. Yu R, Melmed S. Oncogene activation in pituitary tumors. Brain Pathol. 2001;11:328–41.

    Article  CAS  PubMed  Google Scholar 

  12. Ptashne M. How eukaryotic transcriptional activators work. Nature. 1988;335:683–89.

    Article  CAS  PubMed  Google Scholar 

  13. Heaney AP, Singson R, McCabe CJ, Nelson V, Nakashima M, Melmed S. Expression of pituitary-tumour transforming gene in colorectal tumours. Lancet. 2000;355:716–9.

    Article  CAS  PubMed  Google Scholar 

  14. Solbach C, Roller M, Fellbaum C, Nicoletti M, Kaufmann M. PTTG mRNA expression in primary breast cancer: a prognostic marker for lymph node invasion and tumor recurrence. Breast. 2004;13:80–1.

    Article  PubMed  Google Scholar 

  15. Heaney AP, Nelson V, Fernando M, Horwitz G. Transforming events in thyroid tumorigenesis and their association with follicular lesions. J Clin Endocrinol Metab. 2001;86:5025–32.

    Article  CAS  PubMed  Google Scholar 

  16. Su MC, Hsu HC, Liu YJ, Jeng YM. Overexpression of pituitary tumor-transforming gene-1 in hepatocellular carcinoma. Hepatogastroenterology. 2006;53:262–5.

    CAS  PubMed  Google Scholar 

  17. Zhang X, Horwitz GA, Prezant TR, Valentini A, Nakashima M, Bronstein MD, et al. Structure, expression, and function of human pituitary tumor-transforming gene (PTTG). Mol Endocrinol. 1999;13:156–66.

    Article  CAS  PubMed  Google Scholar 

  18. Ishikawa H, Heaney AP, Yu R, Horwitz GA, Melmed S. Human pituitary tumor-transforming gene induces angiogenesis. J Clin Endocrinol Metab. 2001;86:867–74.

    CAS  PubMed  Google Scholar 

  19. Malik MT, Kakar SS. Regulation of angiogenesis and invasion by human Pituitary tumor transforming gene (PTTG) through increased expression and secretion of matrix metalloproteinase-2 (MMP-2). Mol Cancer. 2006;5:61.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Wierinckx A, Auger C, Devauchelle P, Reynaud A, Chevallier P, Jan M, et al. A diagnostic marker set for invasion, proliferation, and aggressiveness of prolactin pituitary tumors. Endocr Relat Cancer. 2007;14:887–900.

    Article  CAS  PubMed  Google Scholar 

  21. Filippella M, Galland F, Kujas M, Young J, Faggiano A, Lombardi G, et al. Pituitary tumour transforming gene (PTTG) expression correlates with the proliferative activity and recurrence status of pituitary adenomas: a clinical and immunohistochemical study. Clin Endocrinol (Oxf). 2006;65:536–43.

    Article  PubMed  Google Scholar 

  22. Frame S, Cohen P, Biondi RM. A common phosphate binding site explains the unique substrate specificity of GSK3 and its inactivation by phosphorylation. Mol Cell. 2001;7:1321–7.

    Article  CAS  PubMed  Google Scholar 

  23. Bialojan C, Takai A. Inhibitory effect of a marine-sponge toxin, okadaic acid, on protein phosphatases. Specif Kinet Biochem J. 1988;256:283–90.

    CAS  Google Scholar 

  24. Cohen P, Holmes CF, Tsukitani Y. Okadaic acid: a new probe for the study of cellular regulation. Trends Biochem Sci. 1990;15:98–102.

    Article  CAS  PubMed  Google Scholar 

  25. Spee B, Carpino G, Schotanus BA, Katoonizadeh A, Vander Borght S, Gaudio E, et al. Characterisation of the liver progenitor cell niche in liver diseases: potential involvement of Wnt and Notch signalling. Gut. 2010;59:247–57.

    Article  PubMed  Google Scholar 

  26. Bruix J, Gores GJ, Mazzaferro V. Hepatocellular carcinoma: clinical frontiers and perspectives. Gut. 2014;63:844–55.

    Article  CAS  PubMed  Google Scholar 

  27. Sharma M, Jamieson C, Lui C, Henderson BR. Distinct hydrophobic "patches" in the N- and C-tails of beta-catenin contribute to nuclear transport. Exp Cell Res. 2016;348:132–45.

    Article  CAS  PubMed  Google Scholar 

  28. Chien W, Pei L. A novel binding factor facilitates nuclear translocation and transcriptional activation function of the pituitary tumor-transforming gene product. J Biol Chem. 2000;275:19422–7.

    Article  CAS  PubMed  Google Scholar 

  29. Yuan YF, Zhai R, Liu XM, Khan HA, Zhen YH, Huo LJ. SUMO-1 plays crucial roles for spindle organization, chromosome congression, and chromosome segregation during mouse oocyte meiotic maturation. Mol Reprod Dev. 2014;81:712–24.

    CAS  PubMed  Google Scholar 

  30. Vega-Rubin-de-Celis S, Peña-Llopis S, Konda M, Brugarolas J. Multistep regulation of TFEB by MTORC1. Autophagy. 2017;13:464–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Köster M, Hauser H. Dynamic redistribution of STAT1 protein in IFN signaling visualized by GFP fusion proteins. Eur J Biochem. 1999;260:137–44.

    Article  PubMed  Google Scholar 

  32. Schmidt KN, Traenckner EB, Meier B, Baeuerle PA. Induction of oxidative stress by okadaic acid is required for activation of transcription factor NF-kappa B. J Biol Chem. 1995;270:27136–42.

    Article  CAS  PubMed  Google Scholar 

  33. Fujita M, Goto K, Yoshida K, Okamura H, Morimoto H, Kito S, et al. Okadaic acid stimulates expression of Fas receptor and Fas ligand by activation of nuclear factor kappa-B in human oral squamous carcinoma cells. Oral Oncol. 2004;40:199–206.

    Article  CAS  PubMed  Google Scholar 

  34. Migone F, Deinnocentes P, Smith BF, Bird RC. Alterations in CDK1 expression and nuclear/nucleolar localization following induction in a spontaneous canine mammary cancer model. J Cell Biochem. 2006;98:504–18.

    Article  CAS  PubMed  Google Scholar 

  35. Lee KK, Yonehara S. Phosphorylation and dimerization regulate nucleocytoplasmic shuttling of mammalian STE20-like kinase (MST). J Biol Chem. 2002;277:12351–8.

    Article  CAS  PubMed  Google Scholar 

  36. Mu YM, Oba K, Yanase T, Ito T, Ashida K, Goto K, et al. Human pituitary tumor transforming gene (hPTTG) inhibits human lung cancer A549 cell growth through activation of p21(WAF1/CIP1). Endocr J. 2003;50:771–81.

    Article  CAS  PubMed  Google Scholar 

  37. Domínguez A, Ramos-Morales F, Romero F, Rios RM, Dreyfus F, Tortolero M, et al. hpttg, a human homologue of rat pttg, is overexpressed in hematopoietic neoplasms. Evidence for a transcriptional activation function of hPTTG. Oncogene. 1998;17:2187–93.

    Article  PubMed  Google Scholar 

  38. MacDonald BT, Tamai K, He X. Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell. 2009;17:9–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Valenta T, Hausmann G, Basler K. The many faces and functions of β-catenin. Embo J. 2012;31:2714–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Suh EK, Gumbiner BM. Translocation of beta-catenin into the nucleus independent of interactions with FG-rich nucleoporins. Exp Cell Res. 2003;290:447–56.

    Article  CAS  PubMed  Google Scholar 

  41. Henderson BR, Fagotto F. The ins and outs of APC and beta-catenin nuclear transport. EMBO Rep. 2002;3:834–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Fagotto F, Glück U, Gumbiner BM. Nuclear localization signal-independent and importin/karyopherin-independent nuclear import of beta-catenin. Curr Biol. 1998;8:181–90.

    Article  CAS  PubMed  Google Scholar 

  43. Henderson BR. Nuclear-cytoplasmic shuttling of APC regulates beta-catenin subcellular localization and turnover. Nat Cell Biol. 2000;2:653–60.

    Article  CAS  PubMed  Google Scholar 

  44. Lu Y, Xie S, Zhang W, Zhang C, Gao C, Sun Q, et al. Twa1/Gid8 is a β-catenin nuclear retention factor in Wnt signaling and colorectal tumorigenesis. Cell Res. 2017;27:1422–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Townsley FM, Cliffe A, Bienz M. Pygopus and Legless target Armadillo/beta-catenin to the nucleus to enable its transcriptional co-activator function. Nat Cell Biol. 2004;6:626–33.

    Article  CAS  PubMed  Google Scholar 

  46. Vlotides G, Eigler T, Melmed S. Pituitary tumor-transforming gene: physiology and implications for tumorigenesis. Endocr Rev. 2007;28:165–86.

    Article  CAS  PubMed  Google Scholar 

  47. Amit S, Hatzubai A, Birman Y, Andersen JS, Ben-Shushan E, Mann M, et al. Axin-mediated CKI phosphorylation of beta-catenin at Ser 45: a molecular switch for the Wnt pathway. Genes Dev. 2002;16:1066–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Zhang W, Yang J, Liu Y, Chen X, Yu T, Jia J, et al. PR55 alpha, a regulatory subunit of PP2A, specifically regulates PP2A-mediated beta-catenin dephosphorylation. J Biol Chem. 2009;284:22649–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Welsh GI, Proud CG. Glycogen synthase kinase-3 is rapidly inactivated in response to insulin and phosphorylates eukaryotic initiation factor eIF-2B. Biochem J. 1993;294:625–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Chai S, Ng KY, Tong M, Lau EY, Lee TK, Chan KW, et al. Octamer 4/microRNA-1246 signaling axis drives Wnt/β-catenin activation in liver cancer stem cells. Hepatology .2016;64:2062–76.

    Article  CAS  PubMed  Google Scholar 

  51. Lee K, Lindsey AS, Li N, Gary B, Andrews J, Keeton AB, et al. β-catenin nuclear translocation in colorectal cancer cells is suppressed by PDE10A inhibition, cGMP elevation, and activation of PKG. Oncotarget. 2016;7:5353–65.

    Article  PubMed  Google Scholar 

  52. Zulehner G, Mikula M, Schneller D, van Zijl F, Huber H, Sieghart W, et al. Nuclear beta-catenin induces an early liver progenitor phenotype in hepatocellular carcinoma and promotes tumor recurrence. Am J Pathol. 2010;176:472–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Zhou C, Zhu X, Liu N, Dong X, Zhang X, Huang H, et al. B-lymphoid tyrosine kinase-mediated FAM83A phosphorylation elevates pancreatic tumorigenesis through interacting with β-catenin. Signal Transduct Target Ther. 2023;8:66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Zhou C, Zhang Y, Dai J, Zhou M, Liu M, Wang Y, et al. Pygo2 functions as a prognostic factor for glioma due to its up-regulation of H3K4me3 and promotion of MLL1/MLL2 complex recruitment. Sci Rep. 2016;6:22066.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Wang L, Wei D, Huang S, Peng Z, Le X, Wu TT, et al. Transcription factor Sp1 expression is a significant predictor of survival in human gastric cancer. Clin Cancer Res. 2003;9:6371–80.

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank the Hubei University of Technology for the research equipment and technical support for this research.

Funding

This work was supported by the National Natural Science Foundation of China (32270768 to C.F.Z, 32070726 and 82273970 to J.F.T, 31871176 to X.Z.C), National Natural Science Foundation of Hubei (2022EHB038 to C.F.Z), Innovation Group Project of Hubei Province (ZRQT2023000075). Wuhan Science and Technology Project (2022020801020272 to C.F.Z).

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Authors and Affiliations

  1. National “111” Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei Key Laboratory of Industrial Microbiology, Hubei University of Technology, Wuhan, China

    Xuewen Zhang, Nianping Wu, Huili Huang, Shi Li, Shicheng Liu, Rui Zhang, Yuan Huang, Hao Lyu, Shuai Xiao, Cefan Zhou & Jingfeng Tang

  2. Department of Biological Sciences, University of Alberta, Edmonton, AB, T6G2R3, Canada

    Declan William Ali & Cefan Zhou

  3. Department of Biochemistry, University of Alberta, Edmonton, AB, T6G2R3, Canada

    Marek Michalak

  4. Membrane Protein Disease Research Group, Department of Physiology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, T6G2R3, Canada

    Xing-Zhen Chen

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Contributions

XWZ wrote the main manuscript and performed molecular biology experiments. JFT and CFZ designed the whole project and supervised all experiments. XWZ, NPW, HLH, SL, SCL, RZ, YH, HL and SX conducted all experiments and analyzed the data. DWA, MM and XZC provided support with experimental and clinical techniques. All authors have read and approved the article.

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Correspondence to Cefan Zhou or Jingfeng Tang.

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Zhang, X., Wu, N., Huang, H. et al. Phosphorylated PTTG1 switches its subcellular distribution and promotes β-catenin stabilization and subsequent transcription activity. Oncogene 42, 2439–2455 (2023). https://doi.org/10.1038/s41388-023-02767-7

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