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SENP2 regulated the stability of β-catenin through WWOX in hepatocellular carcinoma cell

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Tumor Biology

Abstract

SUMOylation and deSUMOylation are dynamic mechanisms regulating a spectrum of protein activities. The SUMO proteases (SENP) remove SUMO conjugate from proteins, and their expression is deregulated in cancers. SENP2 has been reported to play a critical role in the control of hepatocellular carcinoma (HCC) cell growth by modulating the stability of β-catenin. However, the underlying mechanism remains largely unknown. Here, we show that the WW domain-containing oxidoreductase (WWOX), a novel inhibitor of the Wnt/β-catenin pathway, is required for stabilization of β-catenin regulated by SENP2 in HCC cells. The transcriptional level of WWOX is tightly regulated by SENP2. Moreover, knockdown of WWOX by siRNA attuned SENP2-induced β-catenin degradation and decreased SENP2-mediated HCC cell proliferation arrest. Taken together, our data suggested that WWOX is a key downstream modulator of the SENP2 tumor suppressor function in HCC cell.

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References

  1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.

    Article  PubMed  Google Scholar 

  2. Maluccio M, Covey A. Recent progress in understanding, diagnosing, and treating hepatocellular carcinoma. CA: Cancer J Clin. 2012;62:394–9.

    Google Scholar 

  3. Geiss-Friedlander R, Melchior F. Concepts in sumoylation: a decade on. Nat Rev Mol Cell Biol. 2007;8:947–56.

    Article  CAS  PubMed  Google Scholar 

  4. Wilkinson KA, Henley JM. Mechanisms, regulation and consequences of protein sumoylation. Biochem J. 2010;428:133–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Sarge KD, Park-Sarge OK. Sumo and its role in human diseases. Int Rev Cell Mol Biol. 2011;288:167–83.

    Article  CAS  PubMed  Google Scholar 

  6. Hwang KW, Won TJ, Kim H, Chun HJ, Chun T, Park Y. Characterization of the regulatory roles of the sumo. Diabetes Metab Res Rev. 2011;27:854–61.

    Article  CAS  PubMed  Google Scholar 

  7. Wei W, Yang P, Pang J, Zhang S, Wang Y, Wang MH, et al. A stress-dependent sumo4 sumoylation of its substrate proteins. Biochem Biophys Res Commun. 2008;375:454–9.

    Article  CAS  PubMed  Google Scholar 

  8. Wang CY, Podolsky R, She JX. Genetic and functional evidence supporting sumo4 as a type 1 diabetes susceptibility gene. Ann N Y Acad Sci. 2006;1079:257–67.

    Article  CAS  PubMed  Google Scholar 

  9. Hannoun Z, Greenhough S, Jaffray E, Hay RT, Hay DC. Post-translational modification by sumo. Toxicology. 2010;278:288–93.

    Article  CAS  PubMed  Google Scholar 

  10. Bawa-Khalfe T, Yeh ET. Sumo losing balance: sumo proteases disrupt sumo homeostasis to facilitate cancer development and progression. Genes Cancer. 2010;1:748–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Yeh ET. Sumoylation and de-sumoylation: wrestling with life’s processes. J Biol Chem. 2009;284:8223–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kim JH, Baek SH. Emerging roles of desumoylating enzymes. Biochim Biophys Acta. 2009;1792:155–62.

    Article  CAS  PubMed  Google Scholar 

  13. Jiang M, Chiu SY, Hsu W. Sumo-specific protease 2 in mdm2-mediated regulation of p53. Cell Death Differ. 2011;18:1005–15.

    Article  CAS  PubMed  Google Scholar 

  14. Chiu SY, Asai N, Costantini F, Hsu W. Sumo-specific protease 2 is essential for modulating p53-mdm2 in development of trophoblast stem cell niches and lineages. PLoS Biol. 2008;6:e310.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Zhang XD, Goeres J, Zhang H, Yen TJ, Porter AC, Matunis MJ. Sumo −2/3 modification and binding regulate the association of cenp-e with kinetochores and progression through mitosis. Mol Cell. 2008;29:729–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Schweizer N, Ferras C, Kern DM, Logarinho E, Cheeseman IM, Maiato H. Spindle assembly checkpoint robustness requires tpr-mediated regulation of mad1/mad2 proteostasis. J Cell Biol. 2013;203:883–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Cubenas-Potts C, Goeres JD, Matunis MJ. Senp1 and Senp2 affect spatial and temporal control of sumoylation in mitosis. Mol Biol Cell. 2013;24:3483–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lu H, Liu B, You S, Chen L, Dongmei Q, Gu M, Lu Y, Chen Y, Zhang F, Yu B: Senp2 regulates mef2a de-sumoylation in an activity dependent manner. Mol Biol Rep. 2012

  19. Kang X, Qi Y, Zuo Y, Wang Q, Zou Y, Schwartz RJ, et al. Sumo-specific protease 2 is essential for suppression of polycomb group protein-mediated gene silencing during embryonic development. Mol Cell. 2010;38:191–201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Shen HJ, Zhu HY, Yang C, Ji F. Senp2 regulates hepatocellular carcinoma cell growth by modulating the stability of beta-catenin. Asian Pac J Cancer Prev: APJCP. 2012;13:3583–7.

    Article  PubMed  Google Scholar 

  21. Tan MY, Mu XY, Liu B, Wang Y, Bao ED, Qiu JX, et al. Sumo-specific protease 2 suppresses cell migration and invasion through inhibiting the expression of mmp13 in bladder cancer cells. Cel Physiol Biochem: Int J Exp Cel Physiol, Biochem, Pharmacol. 2013;32:542–8.

    Article  CAS  Google Scholar 

  22. Nait Achour T, Sentis S, Teyssier C, Philippat A, Lucas A, Corbo L, et al. Transcriptional repression of estrogen receptor alpha signaling by Senp2 in breast cancer cells. Mol Endocrinol (Baltim, Md). 2014;28:183–96.

    Article  Google Scholar 

  23. Bouteille N, Driouch K, Hage PE, Sin S, Formstecher E, Camonis J, et al. Inhibition of the Wnt/beta-catenin pathway by the WWOX tumor suppressor protein. Oncogene. 2009;28:2569–80.

    Article  CAS  PubMed  Google Scholar 

  24. Li YP, Wu CC, Chen WT, Huang YC, Chai CY. The expression and significance of WWOX and beta-catenin in hepatocellular carcinoma. APMIS: Acta Pathol, Microbiol, Immunol Scand. 2013;121:120–6.

    Article  CAS  Google Scholar 

  25. Klaus A, Birchmeier W. Wnt signalling and its impact on development and cancer. Nat Rev Cancer. 2008;8:387–98.

    Article  CAS  PubMed  Google Scholar 

  26. Del Mare S, Kurek KC, Stein GS, Lian JB, Aqeilan RI. Role of the WWOX tumor suppressor gene in bone homeostasis and the pathogenesis of osteosarcoma. Am J Cancer Res. 2011;1:585–94.

    PubMed  PubMed Central  Google Scholar 

  27. Hezova R, Ehrmann J, Kolar Z. WWOX, a new potential tumor suppressor gene. Biomed Pap Med Fac Univ Palacky, Olomouc, Czechoslov. 2007;151:11–5.

    Article  CAS  Google Scholar 

  28. Abdeen SK, Del Mare S, Hussain S, Remaileh MA, Salah Z, Hagan J, Rawahneh M, Pu XA, Russell S, Stein JL, Stein GS, Lian JB, Aqeilan RI: Conditional inactivation of the mouse wwox tumor suppressor gene recapitulates the null phenotype. J Cell Physiol. 2012

  29. Aqeilan RI, Trapasso F, Hussain S, Costinean S, Marshall D, Pekarsky Y, et al. Targeted deletion of WWOX reveals a tumor suppressor function. Proc Natl Acad Sci USA. 2007;104:3949–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Hepatobiliary Surgery, Henan Provincial People’s Hospital, Zhengzhou, 450003, Henan, China

    Qing-Feng Jiang, Yu-Wei Tian, Quan Shen, Huan-Zhou Xue & Ke Li

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  1. Qing-Feng Jiang
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  2. Yu-Wei Tian
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  3. Quan Shen
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  4. Huan-Zhou Xue
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  5. Ke Li
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Correspondence to Ke Li.

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Jiang, QF., Tian, YW., Shen, Q. et al. SENP2 regulated the stability of β-catenin through WWOX in hepatocellular carcinoma cell. Tumor Biol. 35, 9677–9682 (2014). https://doi.org/10.1007/s13277-014-2239-8

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  • DOI: https://doi.org/10.1007/s13277-014-2239-8

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