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

Article metrics


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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7


  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  21. 21.

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

  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.

  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.

  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.

  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.

  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.

  27. 27.

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

  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.

  29. 29.

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

  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.

  31. 31.

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

  32. 32.

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

  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.

  34. 34.

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

  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.

  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.

  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.

  38. 38.

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

  39. 39.

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

  40. 40.

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

  41. 41.

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

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  53. 53.

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

Download references


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

Author information

Correspondence to Hua-Qin Wang.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethics statement

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.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark