Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

LncRNA PVT-1 promotes osteosarcoma cancer stem-like properties through direct interaction with TRIM28 and TSC2 ubiquitination

Oncogene volume 41, pages 5373–5384 (2022)Cite this article

Subjects

Abstract

Osteosarcoma, the most common pediatric bone tumor, is an aggressive heterogeneous malignancy defined by complex chromosomal aberrations. Overall survival rates remain at ~70%, but patients with chemoresistant or metastatic disease have extremely poor outcomes of <30%. A subgroup of tumors harbor amplification of chromosome 8q24.2 and increased expression of the oncogenic long noncoding RNA (lncRNA) Plasmacytoma Variant Translocation-1 (PVT-1), which is associated with an extremely poor clinical prognosis. This study demonstrates that PVT-1 is critical for osteosarcoma tumor-initiation potential. Chromatin Hybridization by RNA Purification analysis identified Tripartite-Motif Containing Family 28 (TRIM28) as a novel PVT-1 binding partner. Mechanistically, co-immunoprecipitation studies showed the PVT-1/TRIM28 complex binds and increases SUMOylation of phosphatidylinositol 3-kinase catalytic subunit type 3 (Vps34), which leads to enhanced ubiquitination and degradation of tumor suppressor complex 2 (TSC2), thus contributing to increased self-renewal and stem cell phenotypes. Furthermore, we identified that osteosarcoma cells with increased PVT-1 have enhanced sensitivity to the SUMOylation inhibitor, TAK-981. Altogether, this study elucidated a role for PVT-1 in the enhancement of cancer stem-like behaviors, including migration and invasion, in osteosarcoma, and identified the novel PVT-1/TRIM28 axis signaling cascade as a potential therapeutic target for osteosarcoma treatment.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: PVT-1 expression in osteosarcoma.
Fig. 2: PVT-1 enhances osteosarcoma growth and metastatic potential.
Fig. 3: PVT-1 induces cancer stem-like phenotypes.
Fig. 4: PVT-1 drives osteosarcoma cancer stem-like behavior through TSC2.
Fig. 5: PVT-1 interacts with TRIM28 which induces cancer stem-like behaviors.
Fig. 6: Mutation of PVT-1/TRIM28 interaction region negates PVT-1-induced behaviors.
Fig. 7: PVT-1/TRIM28 axis is associated with TSC2 ubiquitination.

Similar content being viewed by others

References

  1. Ottaviani G, Jaffe N. The epidemiology of osteosarcoma. Cancer Treat Res. 2009;152:3–13.

    Article  Google Scholar 

  2. Gibbs CP, Kukekov VG, Reith JD, Tchigrinova O, Suslov ON, Scott EW, et al. Stem-like cells in bone sarcomas: implications for tumorigenesis. Neoplasia. 2005;7:967–76.

    Article  CAS  Google Scholar 

  3. Peitzsch C, Tyutyunnykova A, Pantel K, Dubrovska A. Cancer stem cells: the root of tumor recurrence and metastases. Semin Cancer Biol. 2017;44:10–24.

    Article  CAS  Google Scholar 

  4. Brown HK, Tellez-Gabriel M, Heymann D. Cancer stem cells in osteosarcoma. Cancer Lett. 2017;386:189–95.

    Article  CAS  Google Scholar 

  5. Schiavone K, Garnier D, Heymann MF, Heymann D. The heterogeneity of osteosarcoma: the role played by cancer stem cells. Adv Exp Med Biol. 2019;1139:187–200.

    Article  CAS  Google Scholar 

  6. Houthuijzen JM, Daenen LG, Roodhart JM, Voest EE. The role of mesenchymal stem cells in anti-cancer drug resistance and tumour progression. Br J Cancer. 2012;106:1901–6.

    Article  CAS  Google Scholar 

  7. Al-Romaih K, Bayani J, Vorobyova J, Karaskova J, Park PC, Zielenska M, et al. Chromosomal instability in osteosarcoma and its association with centrosome abnormalities. Cancer Genet Cytogenet. 2003;144:91–9.

    Article  CAS  Google Scholar 

  8. Muff R, Rath P, Ram Kumar RM, Husmann K, Born W, Baudis M, et al. Genomic instability of osteosarcoma cell lines in culture: impact on the prediction of metastasis relevant genes. PLoS ONE. 2015;10:e0125611.

    Article  Google Scholar 

  9. Mirabello L, Berndt SI, Seratti GF, Burdett L, Yeager M, Chowdhury S, et al. Genetic variation at chromosome 8q24 in osteosarcoma cases and controls. Carcinogenesis. 2010;31:1400–4.

    Article  CAS  Google Scholar 

  10. Colombo T, Farina L, Macino G, Paci P. PVT1: a rising star among oncogenic long noncoding RNAs. BioMed Res Int. 2015;2015:304208.

    Article  Google Scholar 

  11. Graham M, Adams JM. Chromosome 8 breakpoint far 3’ of the c-myc oncogene in a Burkitt’s lymphoma 2;8 variant translocation is equivalent to the murine pvt-1 locus. EMBO J. 1986;5:2845–51.

    Article  CAS  Google Scholar 

  12. Feng Y, Hu X, Zhang Y, Zhang D, Li C, Zhang L. Methods for the study of long noncoding RNA in cancer cell signaling. Methods Mol Biol. 2014;1165:115–43.

    Article  Google Scholar 

  13. Han D, Wang M, Ma N, Xu Y, Jiang Y, Gao X. Long noncoding RNAs: novel players in colorectal cancer. Cancer Lett. 2015;361:13–21.

    Article  CAS  Google Scholar 

  14. Huarte M. The emerging role of lncRNAs in cancer. Nat Med. 2015;21:1253–61.

    Article  CAS  Google Scholar 

  15. Du P, Hu C, Qin Y, Zhao J, Patel R, Fu Y, et al. LncRNA PVT1 mediates antiapoptosis and 5-fluorouracil resistance via increasing Bcl2 expression in gastric cancer. J Oncol. 2019;2019:10.

    Article  Google Scholar 

  16. Fan H, Zhu JH, Yao XQ. Knockdown of long noncoding RNA PVT1 reverses multidrug resistance in colorectal cancer cells. Mol Med Rep. 2018;17:8309–15.

    CAS  Google Scholar 

  17. Fu C, Li D, Zhang X, Liu N, Chi G, Jin X. LncRNA PVT1 facilitates tumorigenesis and progression of glioma via regulation of MiR-128-3p/GREM1 axis and BMP signaling pathway. NeuroTherapeutics. 2018;15:1139–57.

    Article  CAS  Google Scholar 

  18. Ping G, Xiong W, Zhang L, Li Y, Zhang Y, Zhao Y. Silencing long noncoding RNA PVT1 inhibits tumorigenesis and cisplatin resistance of colorectal cancer. Am J Transl Res. 2018;10:138–49.

    CAS  Google Scholar 

  19. Carramusa L, Contino F, Ferro A, Minafra L, Perconti G, Giallongo A, et al. The PVT-1 oncogene is a Myc protein target that is overexpressed in transformed cells. J Cell Physiol. 2007;213:511–8.

    Article  CAS  Google Scholar 

  20. Nomura M, Rainusso N, Lee YC, Dawson B, Coarfa C, Han R, et al. Tegavivint and the β-Catenin/ALDH axis in chemotherapy-resistant and metastatic osteosarcoma. J Natl Cancer Inst. 2019;111:1216–27.

    Article  CAS  Google Scholar 

  21. Rainusso N, Cleveland H, Hernandez JA, Quintanilla NM, Hicks J, Vasudevan S, et al. Generation of patient-derived tumor xenografts from percutaneous tumor biopsies in children with bone sarcomas. Pediatr Blood Cancer. 2019;66:e27579.

    Google Scholar 

  22. Chen S, Zhu J, Wang F, Guan Z, Ge Y, Yang X, et al. LncRNAs and their role in cancer stem cells. Oncotarget. 2017;8:110685–92.

    Article  Google Scholar 

  23. Chan KS, Espinosa I, Chao M, Wong D, Ailles L, Diehn M, et al. Identification, molecular characterization, clinical prognosis, and therapeutic targeting of human bladder tumor-initiating cells. Proc Natl Acad Sci USA. 2009;106:14016–21.

    Article  CAS  Google Scholar 

  24. Madsen RR. PI3K in stemness regulation: from development to cancer. Biochem Soc Trans. 2020;48:301–15.

    Article  CAS  Google Scholar 

  25. Xia P, Xu XY. PI3K/Akt/mTOR signaling pathway in cancer stem cells: from basic research to clinical application. Am J Cancer Res. 2015;5:1602–9.

    Google Scholar 

  26. Wang F, Yuan JH, Wang SB, Yang F, Yuan SX, Ye C, et al. Oncofetal long noncoding RNA PVT1 promotes proliferation and stem cell-like property of hepatocellular carcinoma cells by stabilizing NOP2. Hepatology. 2014;60:1278–90.

    Article  CAS  Google Scholar 

  27. Czerwińska P, Shah PK, Tomczak K, Klimczak M, Mazurek S, Sozańska B, et al. TRIM28 multi-domain protein regulates cancer stem cell population in breast tumor development. Oncotarget. 2017;8:863–82.

    Article  Google Scholar 

  28. Li J, Xi Y, Li W, McCarthy RL, Stratton SA, Zou W, et al. TRIM28 interacts with EZH2 and SWI/SNF to activate genes that promote mammosphere formation. Oncogene. 2017;36:2991–3001.

    Article  CAS  Google Scholar 

  29. Brisbin AG, Asmann YW, Song H, Tsai YY, Aakre JA, Yang P, et al. Meta-analysis of 8q24 for seven cancers reveals a locus between NOV and ENPP2 associated with cancer development. BMC Med Genet. 2011;12:156.

    Article  CAS  Google Scholar 

  30. Letessier A, Sircoulomb F, Ginestier C, Cervera N, Monville F, Gelsi-Boyer V, et al. Frequency, prognostic impact, and subtype association of 8p12, 8q24, 11q13, 12p13, 17q12, and 20q13 amplifications in breast cancers. BMC Cancer. 2006;6:245.

    Article  Google Scholar 

  31. Tang J, Li Y, Sang Y, Yu B, Lv D, Zhang W, et al. LncRNA PVT1 regulates triple-negative breast cancer through KLF5/beta-catenin signaling. Oncogene. 2018;37:4723–34.

    Article  CAS  Google Scholar 

  32. Wang H, Huang Y, Yang Y. LncRNA PVT1 regulates TRPS1 expression in breast cancer by sponging miR-543. Cancer Manag Res. 2020;12:7993–8004.

    Article  CAS  Google Scholar 

  33. Lang B, Armaos A, Tartaglia GG. RNAct: protein-RNA interaction predictions for model organisms with supporting experimental data. Nucleic Acids Res. 2019;47:D601–d6.

    Article  CAS  Google Scholar 

  34. Livi CM, Klus P, Delli Ponti R, Tartaglia GG. catRAPID signature: identification of ribonucleoproteins and RNA-binding regions. Bioinformatics. 2016;32:773–5.

    Article  CAS  Google Scholar 

  35. Mohan N, Shen Y, Dokmanovic M, Endo Y, Hirsch DS, Wu WJ. VPS34 regulates TSC1/TSC2 heterodimer to mediate RheB and mTORC1/S6K1 activation and cellular transformation. Oncotarget. 2016;7:52239–54.

    Article  Google Scholar 

  36. Yang Y, Fiskus W, Yong B, Atadja P, Takahashi Y, Pandita TK, et al. Acetylated hsp70 and KAP1-mediated Vps34 SUMOylation is required for autophagosome creation in autophagy. Proc Natl Acad Sci USA. 2013;110:6841–6.

    Article  CAS  Google Scholar 

  37. Langston SP, Grossman S, England D, Afroze R, Bence N, Bowman D, et al. Discovery of TAK-981, a first-in-class inhibitor of SUMO-activating enzyme for the treatment of cancer. J Med Chem. 2021;64:2501–20.

    Article  CAS  Google Scholar 

  38. Misaghi A, Goldin A, Awad M, Kulidjian AA. Osteosarcoma: a comprehensive review. SICOT-J. 2018;4:12.

    Article  Google Scholar 

  39. Pradhan SA, Rather MI, Tiwari A, Bhat VK, Kumar A. Evidence that TSC2 acts as a transcription factor and binds to and represses the promoter of Epiregulin. Nucleic Acids Res. 2014;42:6243–55.

    Article  CAS  Google Scholar 

  40. Moschos SJ, Smith AP, Mandic M, Athanassiou C, Watson-Hurst K, Jukic DM, et al. SAGE and antibody array analysis of melanoma-infiltrated lymph nodes: identification of Ubc9 as an important molecule in advanced-stage melanomas. Oncogene. 2007;26:4216–25.

    Article  CAS  Google Scholar 

  41. Adriaens C, Standaert L, Barra J, Latil M, Verfaillie A, Kalev P, et al. p53 induces formation of NEAT1 lncRNA-containing paraspeckles that modulate replication stress response and chemosensitivity. Nat Med. 2016;22:861–8.

    Article  CAS  Google Scholar 

  42. Fan Y, Shen B, Tan M, Mu X, Qin Y, Zhang F, et al. TGF-beta-induced upregulation of malat1 promotes bladder cancer metastasis by associating with suz12. Clin Cancer Res. 2014;20:1531–41.

    Article  CAS  Google Scholar 

  43. Assouline S, Mehta A, Caimi PF, Wang B, Patel C, Kim M-S, et al. A phase 1b/2 study of TAK-981, a first-in-class sumoylation inhibitor, in combination with rituximab in patients with relapsed/refractory (r/r) CD20-positive non-Hodgkin lymphoma (NHL). Blood. 2019;134:1593.

    Article  Google Scholar 

  44. Liu X, Xu Y, Pang Z, Guo F, Qin Q, Yin T, et al. Knockdown of SUMO-activating enzyme subunit 2 (SAE2) suppresses cancer malignancy and enhances chemotherapy sensitivity in small cell lung cancer. J Hematol Oncol. 2015;8:67.

    Article  Google Scholar 

  45. Fong KW, Zhao JC, Song B, Zheng B, Yu J. TRIM28 protects TRIM24 from SPOP-mediated degradation and promotes prostate cancer progression. Nat Commun. 2018;9:5007.

    Article  Google Scholar 

  46. Dasgupta A, Sierra L, Tsang SV, Kurenbekova L, Patel T, Rajapakse K, et al. Targeting PAK4 inhibits Ras-mediated signaling and multiple oncogenic pathways in high-risk rhabdomyosarcoma. Cancer Res. 2021;81:199–212.

    Article  CAS  Google Scholar 

  47. Chu C, Zhang QC, da Rocha ST, Flynn RA, Bharadwaj M, Calabrese JM, et al. Systematic discovery of Xist RNA binding proteins. Cell. 2015;161:404–16.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We would like to acknowledge the Advanced Technologies Core services at the Baylor College of Medicine. This work was funded by The Faris D. Virani Ewing Sarcoma Center (to JTY). SVT was partially supported by Cancer Prevention Institute of Texas (CPRIT) RP160283, KR and CC were partially supported by (CPRIT) RP170005, NIH P30 shared resource grant CA125123, and NIEHS P30 Center grant 1P30ES030285; CPRIT Core Facility Support Award (CPRIT-RP180672), the NIH (CA125123 and RR024574 to the Cytometry and Cell Sorting Core at Baylor College of Medicine); and Core Facility Award (CPRIT-RP170005 to Proteomics and Metabolomics Core at Baylor College of Medicine). We thank Dr. Suzanne Fuqua and Dr. Xiang Zhang for generously providing the breast cancer cell lines.

Author information

Author notes

  1. Jason T. Yustein

    Present address: Aflac Cancer and Blood Disorders Center, Emory University, Atlanta, GA, 30322, USA

Authors and Affiliations

  1. Texas Children’s Cancer and Hematology Centers and The Faris D. Virani Ewing Sarcoma Center, Baylor College of Medicine, Houston, TX, 77030, USA

    Susan V. Tsang, Nino Rainusso, Meng Liu, Tajhal D. Patel, Kengo Nakahata, Ha Ram Kim, Tsz-Kwong Man, Pulivarthi H. Rao & Jason T. Yustein

  2. Integrative Molecular and Biomedical Sciences Program, Baylor College of Medicine, Houston, TX, 77030, USA

    Susan V. Tsang & Jason T. Yustein

  3. Dan L. Duncan Cancer Comprehensive Center, Baylor College of Medicine, Houston, TX, 77030, USA

    Nino Rainusso, Cristian Coarfa & Jason T. Yustein

  4. Department of Pediatric Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan

    Motonari Nomura & Kengo Nakahata

  5. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA

    Shixia Huang & Cristian Coarfa

  6. Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

    Kimal Rajapakshe

  7. Cancer and Cell Biology Program, Baylor College of Medicine, Houston, TX, 77030, USA

    Cristian Coarfa & Jason T. Yustein

Authors
  1. Susan V. Tsang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nino Rainusso
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Meng Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Motonari Nomura
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tajhal D. Patel
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kengo Nakahata
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ha Ram Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shixia Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Kimal Rajapakshe
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Cristian Coarfa
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Tsz-Kwong Man
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Pulivarthi H. Rao
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Jason T. Yustein
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

SVT and JTY conceived the project. SVT, TDP, KR, CC, TKM, PHR, and JTY designed the experiments and analyzed the data. SVT, NR, ML, MN, KN, HRK, and SH performed the experiments, in part, and analyzed the data. JTY supervised the study. SVT and JTY wrote and revised the manuscript. All authors reviewed and approved the paper.

Corresponding author

Correspondence to Jason T. Yustein.

Ethics declarations

Competing interests

The authors declare no competing interests.

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

Springer Nature or its licensor (e.g., a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tsang, S.V., Rainusso, N., Liu, M. et al. LncRNA PVT-1 promotes osteosarcoma cancer stem-like properties through direct interaction with TRIM28 and TSC2 ubiquitination. Oncogene 41, 5373–5384 (2022). https://doi.org/10.1038/s41388-022-02538-w

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-022-02538-w

This article is cited by

Search

Advanced search

Quick links