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Loss of TRIM29 suppresses cancer stem cell-like characteristics of PDACs via accelerating ISG15 degradation


TRIM family proteins are defined as E3 ubiquitin ligases because of their RING-finger domains. The ubiquitin-like protein interferon-stimulated gene 15 (ISG15) encodes a 15-kDa protein, that is implicated in the posttranslational modification of diverse proteins. Both TRIM29 and ISG15 play both pro-tumoral and anti-tumoral functions in cancer cells derived from different histology. In the current study, we demonstrated that correlation expression of TRIM29 and ISG15 in pancreatic ductal adenocarcinomas (PDACs). The current study demonstrated that TRIM29 knockdown destabilized ISG15 protein via promoting its processing by calpain 3 (CAPN3). Importantly, the current study found that TRIM29 knockdown suppressed cancer stem cell-like features of PDACs, which can be rescued by ISG15 independent of its conjugation function. In addition, the current study demonstrated that extracellular free ISG15 played an important role in maintenance of cancer stem cell-like features of PDACs. Thereby, the current study displayed a novel mechanism by which TRIM29 modulates ISG15 stability via CAPN3-mediated processing, and subsequently extracellular ISG15 maintains the cancer stem cell-like features of PDAC via autocrine mode of action.

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  1. 1.

    Kapp LN, Painter RB, Yu LC, van Loon N, Richard CW 3rd, James MR, et al. Cloning of a candidate gene for ataxia-telangiectasia group D. Am J Hum Genet. 1992;51:45–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Reymond A, Meroni G, Fantozzi A, Merla G, Cairo S, Luzi L, et al. The tripartite motif family identifies cell compartments. EMBO J. 2001;20:2140–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Jiang T, Tang HM, Lu S, Yan DW, Yang YX, Peng ZH. Up-regulation of tripartite motif-containing 29 promotes cancer cell proliferation and predicts poor survival in colorectal cancer. Med Oncol. 2013;30:715.

    PubMed  Google Scholar 

  4. 4.

    Song X, Fu C, Yang X, Sun D, Zhang X, Zhang J. Tripartite motif-containing 29 as a novel biomarker in non-small cell lung cancer. Oncol Lett. 2015;10:2283–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Tan ST, Liu SY, Wu B. TRIM29 overexpression promotes proliferation and survival of bladder cancer cells through NF-kappaB signaling. Cancer Res Treat. 2016;48:1302–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Xu R, Hu J, Zhang T, Jiang C, Wang HY. TRIM29 overexpression is associated with poor prognosis and promotes tumor progression by activating Wnt/beta-catenin pathway in cervical cancer. Oncotarget. 2016;7:28579–91.

    PubMed  PubMed Central  Google Scholar 

  7. 7.

    Zhou XM, Sun R, Luo DH, Sun J, Zhang MY, Wang MH, et al. Upregulated TRIM29 promotes proliferation and metastasis of nasopharyngeal carcinoma via PTEN/AKT/mTOR signal pathway. Oncotarget. 2016;7:13634–50.

    PubMed  PubMed Central  Google Scholar 

  8. 8.

    Kosaka Y, Inoue H, Ohmachi T, Yokoe T, Matsumoto T, Mimori K, et al. Tripartite motif-containing 29 (TRIM29) is a novel marker for lymph node metastasis in gastric cancer. Ann Surg Oncol. 2007;14:2543–9.

    PubMed  Google Scholar 

  9. 9.

    Mutter GL, Baak JP, Fitzgerald JT, Gray R, Neuberg D, Kust GA, et al. Global expression changes of constitutive and hormonally regulated genes during endometrial neoplastic transformation. Gynecol Oncol. 2001;83:177–85.

    CAS  PubMed  Google Scholar 

  10. 10.

    Ai L, Kim WJ, Alpay M, Tang M, Pardo CE, Hatakeyama S, et al. TRIM29 suppresses TWIST1 and invasive breast cancer behavior. Cancer Res. 2014;74:4875–87.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Yanagi T, Watanabe M, Hata H, Kitamura S, Imafuku K, Yanagi H, et al. Loss of TRIM29 alters keratin distribution to promote cell invasion in squamous cell carcinoma. Cancer Res. 2018;78:6795–806.

    CAS  PubMed  Google Scholar 

  12. 12.

    Wang L, Heidt DG, Lee CJ, Yang H, Logsdon CD, Zhang L, et al. Oncogenic function of ATDC in pancreatic cancer through Wnt pathway activation and beta-catenin stabilization. Cancer Cell. 2009;15:207–19.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Yuan Z, Villagra A, Peng L, Coppola D, Glozak M, Sotomayor EM, et al. The ATDC (TRIM29) protein binds p53 and antagonizes p53-mediated functions. Mol Cell Biol. 2010;30:3004–15.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Wang L, Yang H, Abel EV, Ney GM, Palmbos PL, Bednar F, et al. ATDC induces an invasive switch in KRAS-induced pancreatic tumorigenesis. Genes Dev. 2015;29:171–83.

    PubMed  PubMed Central  Google Scholar 

  15. 15.

    Valle S, Martin-Hijano L, Alcala S, Alonso-Nocelo M, Sainz B, Jr. The ever-evolving concept of the cancer stem cell in pancreatic cancer. Cancers. (2018); 10.

  16. 16.

    Balic A, Dorado J, Alonso-Gomez M, Heeschen C. Stem cells as the root of pancreatic ductal adenocarcinoma. Exp Cell Res. 2012;318:691–704.

    CAS  PubMed  Google Scholar 

  17. 17.

    Chronopoulos A, Robinson B, Sarper M, Cortes E, Auernheimer V, Lachowski D, et al. ATRA mechanically reprograms pancreatic stellate cells to suppress matrix remodelling and inhibit cancer cell invasion. Nat Commun. 2016;7:12630.

    PubMed  PubMed Central  Google Scholar 

  18. 18.

    Sainz B Jr., Martin B, Tatari M, Heeschen C, Guerra S. ISG15 is a critical microenvironmental factor for pancreatic cancer stem cells. Cancer Res. 2014;74:7309–20.

    CAS  PubMed  Google Scholar 

  19. 19.

    Sainz B Jr., Carron E, Vallespinos M, Machado HL. Cancer stem cells and macrophages: implications in tumor biology and therapeutic strategies. Mediat Inflamm. 2016;2016:9012369.

    Google Scholar 

  20. 20.

    Haas AL, Ahrens P, Bright PM, Ankel H. Interferon induces a 15-kilodalton protein exhibiting marked homology to ubiquitin. J Biol Chem. 1987;262:11315–23.

    CAS  PubMed  Google Scholar 

  21. 21.

    Loeb KR, Haas AL. The interferon-inducible 15-kDa ubiquitin homolog conjugates to intracellular proteins. J Biol Chem. 1992;267:7806–13.

    CAS  PubMed  Google Scholar 

  22. 22.

    Pattyn E, Verhee A, Uyttendaele I, Piessevaux J, Timmerman E, Gevaert K, et al. HyperISGylation of Old World monkey ISG15 in human cells. PLoS ONE. 2008;3:e2427.

    PubMed  PubMed Central  Google Scholar 

  23. 23.

    Charton K, Sarparanta J, Vihola A, Milic A, Jonson PH, Suel L, et al. CAPN3-mediated processing of C-terminal titin replaced by pathological cleavage in titinopathy. Hum Mol Genet. 2015;24:3718–31.

    CAS  PubMed  Google Scholar 

  24. 24.

    Giannakopoulos NV, Arutyunova E, Lai C, Lenschow DJ, Haas AL, Virgin HW. ISG15 Arg151 and the ISG15-conjugating enzyme UbE1L are important for innate immune control of Sindbis virus. J Virol. 2009;83:1602–10.

    CAS  PubMed  Google Scholar 

  25. 25.

    Lenschow DJ, Giannakopoulos NV, Gunn LJ, Johnston C, O’Guin AK, Schmidt RE, et al. Identification of interferon-stimulated gene 15 as an antiviral molecule during Sindbis virus infection in vivo. J Virol. 2005;79:13974–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Burks J, Reed RE, Desai SD. Free ISG15 triggers an antitumor immune response against breast cancer: a new perspective. Oncotarget. 2015;6:7221–31.

    PubMed  PubMed Central  Google Scholar 

  27. 27.

    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68:7–30.

    PubMed  Google Scholar 

  28. 28.

    Hermann PC, Huber SL, Herrler T, Aicher A, Ellwart JW, Guba M, et al. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell. 2007;1:313–23.

    CAS  PubMed  Google Scholar 

  29. 29.

    Paget S. The distribution of secondary growths in cancer of the breast. 1889. Cancer Metastas- Rev. 1989;8:98–101.

    CAS  Google Scholar 

  30. 30.

    Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J, et al. Identification of a cancer stem cell in human brain tumors. Cancer Res. 2003;63:5821–8.

    CAS  PubMed  Google Scholar 

  31. 31.

    Vlashi E, Pajonk F. Cancer stem cells, cancer cell plasticity and radiation therapy. Semin Cancer Biol. 2015;31:28–35.

    CAS  PubMed  Google Scholar 

  32. 32.

    Vries RG, Huch M, Clevers H. Stem cells and cancer of the stomach and intestine. Mol Oncol. 2010;4:373–84.

    PubMed  PubMed Central  Google Scholar 

  33. 33.

    Wang T, Shigdar S, Gantier MP, Hou Y, Wang L, Li Y, et al. Cancer stem cell targeted therapy: progress amid controversies. Oncotarget. 2015;6:44191–206.

    PubMed  PubMed Central  Google Scholar 

  34. 34.

    Hatakeyama S. TRIM family proteins: roles in autophagy, immunity, and carcinogenesis. Trends Biochem Sci. 2017;42:297–311.

    CAS  PubMed  Google Scholar 

  35. 35.

    Sho T, Tsukiyama T, Sato T, Kondo T, Cheng J, Saku T, et al. TRIM29 negatively regulates p53 via inhibition of Tip60. Biochim Biophys Acta. 2011;1813:1245–53.

    CAS  PubMed  Google Scholar 

  36. 36.

    Dukel M, Streitfeld WS, Tang TC, Backman LR, Ai L, May WS, et al. The breast cancer tumor suppressor trim29 is expressed via ATM-dependent signaling in response to hypoxia. J Biol Chem. 2016;291:21541–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Liu J, Welm B, Boucher KM, Ebbert MT, Bernard PS. TRIM29 functions as a tumor suppressor in nontumorigenic breast cells and invasive ER+ breast cancer. Am J Pathol. 2012;180:839–47.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Tanaka K. The proteasome: overview of structure and functions. Proc Jpn Acad Ser B Phys Biol Sci. 2009;85:12–36.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Mizushima N, Levine B. Autophagy in mammalian development and differentiation. Nat Cell Biol. 2010;12:823–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Tait SW, Green DR. Mitochondria and cell death: outer membrane permeabilization and beyond. Nat Rev Mol Cell Biol. 2010;11:621–32.

    CAS  PubMed  Google Scholar 

  41. 41.

    Desai SD. ISG15: a double edged sword in cancer. Oncoimmunology. 2015;4:e1052935.

    PubMed  PubMed Central  Google Scholar 

  42. 42.

    Chen RH, Du Y, Han P, Wang HB, Liang FY, Feng GK, et al. ISG15 predicts poor prognosis and promotes cancer stem cell phenotype in nasopharyngeal carcinoma. Oncotarget. 2016;7:16910–22.

    PubMed  PubMed Central  Google Scholar 

  43. 43.

    Yuan H, Zhou W, Yang Y, Xue L, Liu L, Song Y. ISG15 promotes esophageal squamous cell carcinoma tumorigenesis via c-MET/Fyn/beta-catenin signaling pathway. Exp Cell Res. 2018;367:47–55.

    CAS  PubMed  Google Scholar 

  44. 44.

    Zhang Q, He Y, Nie M, Cai W. Roles of miR-138 and ISG15 in oral squamous cell carcinoma. Exp Ther Med. 2017;14:2329–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Du Z, Cai C, Sims M, Boop FA, Davidoff AM, Pfeffer LM. The effects of type I interferon on glioblastoma cancer stem cells. Biochem Biophys Res Commun. 2017;491:343–8.

    CAS  PubMed  Google Scholar 

  46. 46.

    Feng Q, Sekula D, Guo Y, Liu X, Black CC, Galimberti F, et al. UBE1L causes lung cancer growth suppression by targeting cyclin D1. Mol Cancer Ther. 2008;7:3780–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Jeon YJ, Jo MG, Yoo HM, Hong SH, Park JM, Ka SH, et al. Chemosensitivity is controlled by p63 modification with ubiquitin-like protein ISG15. J Clin Investig. 2012;122:2622–36.

    CAS  PubMed  Google Scholar 

  48. 48.

    Mao H, Wang M, Cao B, Zhou H, Zhang Z, Mao X. Interferon-stimulated gene 15 induces cancer cell death by suppressing the NF-kappaB signaling pathway. Oncotarget. 2016;7:70143–51.

    PubMed  PubMed Central  Google Scholar 

  49. 49.

    Mustachio LM, Lu Y, Kawakami M, Roszik J, Freemantle SJ, Liu X, et al. Evidence for the ISG15-specific deubiquitinase USP18 as an antineoplastic target. Cancer Res. 2018;78:587–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Yoo L, Yoon AR, Yun CO, Chung KC. Covalent ISG15 conjugation to CHIP promotes its ubiquitin E3 ligase activity and inhibits lung cancer cell growth in response to type I interferon. Cell death Dis. 2018;9:97.

    PubMed  PubMed Central  Google Scholar 

  51. 51.

    Zhou MJ, Chen FZ, Chen HC, Wan XX, Zhou X, Fang Q, et al. ISG15 inhibits cancer cell growth and promotes apoptosis. Int J Mol Med. 2017;39:446–52.

    CAS  PubMed  Google Scholar 

  52. 52.

    Desai SD, Reed RE, Burks J, Wood LM, Pullikuth AK, Haas AL, et al. ISG15 disrupts cytoskeletal architecture and promotes motility in human breast cancer cells. Exp Biol Med. 2012;237:38–49.

    CAS  Google Scholar 

  53. 53.

    Burks J, Reed RE, Desai SD. ISGylation governs the oncogenic function of Ki-Ras in breast cancer. Oncogene. 2014;33:794–803.

    CAS  PubMed  Google Scholar 

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This work was partly supported by National Natural Science Foundation of China (81572828, 81602510, and 81602439) and China Postdoctoral Science Foundation (2017M611286).

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Correspondence to Hua-Qin Wang.

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The authors declare that they have no conflict of interest.

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This study was carried out in accordance with the recommendations of Guide for Laboratory Animal Care and Use, Institutional Animal Care and Use Committee of China Medical University. The protocol was approved by the Institutional Animal Care and Use Committee of China Medical University.

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Sun, J., Yan, J., Qiao, HY. et al. Loss of TRIM29 suppresses cancer stem cell-like characteristics of PDACs via accelerating ISG15 degradation. Oncogene 39, 546–559 (2020).

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