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.

USP15 stabilizes TGF-β receptor I and promotes oncogenesis through the activation of TGF-β signaling in glioblastoma

Nature Medicine volume 18, pages 429–435 (2012)Cite this article

Subjects

Abstract

In advanced cancer, including glioblastoma, the transforming growth factor β (TGF-β) pathway acts as an oncogenic factor and is considered to be a therapeutic target. Using a functional RNAi screen, we identified the deubiquitinating enzyme ubiquitin-specific peptidase 15 (USP15) as a key component of the TGF-β signaling pathway. USP15 binds to the SMAD7–SMAD specific E3 ubiquitin protein ligase 2 (SMURF2) complex and deubiquitinates and stabilizes type I TGF-β receptor (TβR-I), leading to an enhanced TGF-β signal. High expression of USP15 correlates with high TGF-β activity, and the USP15 gene is found amplified in glioblastoma, breast and ovarian cancer. USP15 amplification confers poor prognosis in individuals with glioblastoma. Downregulation or inhibition of USP15 in a patient-derived orthotopic mouse model of glioblastoma decreases TGF-β activity. Moreover, depletion of USP15 decreases the oncogenic capacity of patient-derived glioma-initiating cells due to the repression of TGF-β signaling. Our results show that USP15 regulates the TGF-β pathway and is a key factor in glioblastoma pathogenesis.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

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

Figure 1: Identification of USP15 as a regulator of the TGF-β signaling pathway.
Figure 2: USP15 forms a complex with SMAD7 and SMURF2.
Figure 3: USP15 regulates TβR-I stability and counteracts SMURF2 activity.
Figure 4: USP15 regulates the TGF-β signaling pathway in human GBM.
Figure 5: USP15 is targeted for gene amplification.
Figure 6: Knockdown of USP15 inhibits TGF-β activity and the oncogenic potential of patient-derived GBM neurospheres.

References

  1. Furnari, F.B. et al. Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes Dev. 21, 2683–2710 (2007).

    Article  CAS  Google Scholar 

  2. Holland, E.C. Gliomagenesis: genetic alterations and mouse models. Nat. Rev. Genet. 2, 120–129 (2001).

    Article  CAS  Google Scholar 

  3. Maher, E.A. et al. Malignant glioma: genetics and biology of a grave matter. Genes Dev. 15, 1311–1333 (2001).

    Article  CAS  Google Scholar 

  4. Zhu, Y. & Parada, L.F. The molecular and genetic basis of neurological tumours. Nat. Rev. Cancer 2, 616–626 (2002).

    Article  CAS  Google Scholar 

  5. Rich, J.N. The role of transforming growth factor-β in primary brain tumors. Front. Biosci. 8, e245–e260 (2003).

    Article  CAS  Google Scholar 

  6. Bruna, A. et al. High TGFβ-Smad activity confers poor prognosis in glioma patients and promotes cell proliferation depending on the methylation of the PDGF-B gene. Cancer Cell 11, 147–160 (2007).

    Article  CAS  Google Scholar 

  7. Peñuelas, S. et al. TGF-β increases glioma-initiating cell self-renewal through the induction of LIF in human glioblastoma. Cancer Cell 15, 315–327 (2009).

    Article  Google Scholar 

  8. Anido, J. et al. TGF-β receptor inhibitors target the CD44(high)/Id1(high) glioma-initiating cell population in human glioblastoma. Cancer Cell 18, 655–668 (2010).

    Article  CAS  Google Scholar 

  9. Ikushima, H. et al. Autocrine TGF-β signaling maintains tumorigenicity of glioma-initiating cells through Sry-related HMG-box factors. Cell Stem Cell 5, 504–514 (2009).

    Article  CAS  Google Scholar 

  10. Massagué, J., Seoane, J. & Wotton, D. Smad transcription factors. Genes Dev. 19, 2783–2810 (2005).

    Article  Google Scholar 

  11. Itoh, S. & ten Dijke, P. Negative regulation of TGF-β receptor/Smad signal transduction. Curr. Opin. Cell Biol. 19, 176–184 (2007).

    Article  CAS  Google Scholar 

  12. Wicks, S.J. et al. Reversible ubiquitination regulates the Smad/TGF-β signalling pathway. Biochem. Soc. Trans. 34, 761–763 (2006).

    Article  CAS  Google Scholar 

  13. Kavsak, P. et al. Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGF β receptor for degradation. Mol. Cell 6, 1365–1375 (2000).

    Article  CAS  Google Scholar 

  14. Ogunjimi, A.A. et al. Regulation of Smurf2 ubiquitin ligase activity by anchoring the E2 to the HECT domain. Mol. Cell 19, 297–308 (2005).

    Article  CAS  Google Scholar 

  15. Lee, B.H. et al. Enhancement of proteasome activity by a small-molecule inhibitor of USP14. Nature 467, 179–184 (2010).

    Article  CAS  Google Scholar 

  16. Schweitzer, K., Bozko, P.M., Dubiel, W. & Naumann, M. CSN controls NF-κB by deubiquitinylation of IκBα. EMBO J. 26, 1532–1541 (2007).

    Article  CAS  Google Scholar 

  17. Xu, M. et al. USP15 plays an essential role for caspase-3 activation during Paclitaxel-induced apoptosis. Biochem. Biophys. Res. Commun. 388, 366–371 (2009).

    Article  CAS  Google Scholar 

  18. Huang, X., Langelotz, C., Hetfeld-Pechoc, B.K., Schwenk, W. & Dubiel, W. The COP9 signalosome mediates β-catenin degradation by deneddylation and blocks adenomatous polyposis coli destruction via USP15. J. Mol. Biol. 391, 691–702 (2009).

    Article  CAS  Google Scholar 

  19. Inui, M. et al. USP15 is a deubiquitylating enzyme for receptor-activated SMADs. Nat. Cell Biol. 13, 1368–1375 (2011).

    Article  CAS  Google Scholar 

  20. Brummelkamp, T.R., Bernards, R. & Agami, R. A system for stable expression of short interfering RNAs in mammalian cells. Science 296, 550–553 (2002).

    Article  CAS  Google Scholar 

  21. Nijman, S.M. et al. A genomic and functional inventory of deubiquitinating enzymes. Cell 123, 773–786 (2005).

    Article  CAS  Google Scholar 

  22. Moretti, J. et al. The translation initiation factor 3f (eIF3f) exhibits a deubiquitinase activity regulating Notch activation. PLoS Biol. 8, e1000545 (2010).

    Article  Google Scholar 

  23. Nakao, A. et al. Identification of Smad7, a TGFβ-inducible antagonist of TGF-β signalling. Nature 389, 631–635 (1997).

    Article  CAS  Google Scholar 

  24. Papa, F.R. & Hochstrasser, M. The yeast DOA4 gene encodes a deubiquitinating enzyme related to a product of the human Tre-2 oncogene. Nature 366, 313–319 (1993).

    Article  CAS  Google Scholar 

  25. Ebisawa, T. et al. Smurf1 interacts with transforming growth factor-β type I receptor through Smad7 and induces receptor degradation. J. Biol. Chem. 276, 12477–12480 (2001).

    Article  CAS  Google Scholar 

  26. Wiesner, S. et al. Autoinhibition of the HECT-type ubiquitin ligase Smurf2 through its C2 domain. Cell 130, 651–662 (2007).

    Article  CAS  Google Scholar 

  27. Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455, 1061–1068 (2008).

  28. Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature 474, 609–615 (2011).

  29. Seoane, J. The TGFβ pathway as a therapeutic target in cancer. Clin. Transl. Oncol. 10, 14–19 (2008).

    Article  CAS  Google Scholar 

  30. Rodon et al. First human dose (FHD) study of the oral transforming growth factor-β (TGFβ) receptor I kinase inhibitor LY2157299 in patients with treatment-refractory malignant glioma. J. Clin. Oncol. 29 (suppl.) abstr. 3011 (2011).

  31. Oettle et al. Phase I/II study with trabedersen (AP 1009) monotherapy for the treatment of patients with advanced pancreatic cancer, malignant melanoma, and colorectal carcinoma. Am. Soc. Clin. Oncology (2011).

  32. Zhu, H., Kavsak, P., Abdollah, S., Wrana, J.L. & Thomsen, G.H.A. SMAD ubiquitin ligase targets the BMP pathway and affects embryonic pattern formation. Nature 400, 687–693 (1999).

    Article  CAS  Google Scholar 

  33. Zhang, Y., Chang, C., Gehling, D.J., Hemmati-Brivanlou, A. & Derynck, R. Regulation of Smad degradation and activity by Smurf2, an E3 ubiquitin ligase. Proc. Natl. Acad. Sci. USA 98, 974–979 (2001).

    Article  CAS  Google Scholar 

  34. Hata, A., Lagna, G., Massagué, J. & Hemmati-Brivanlou, A. Smad6 inhibits BMP/Smad1 signaling by specifically competing with the Smad4 tumor suppressor. Genes Dev. 12, 186–197 (1998).

    Article  CAS  Google Scholar 

  35. Kamitani, T., Kito, K., Nguyen, H.P. & Yeh, E.T. Characterization of NEDD8, a developmentally down-regulated ubiquitin-like protein. J. Biol. Chem. 272, 28557–28562 (1997).

    Article  CAS  Google Scholar 

  36. Günther, H.S. et al. Glioblastoma-derived stem cell–enriched cultures form distinct subgroups according to molecular and phenotypic criteria. Oncogene 27, 2897–2909 (2008).

    Article  Google Scholar 

  37. van der Eb, A.J. & Graham, F.L. Assay of transforming activity of tumor virus DNA. Methods Enzymol. 65, 826–839 (1980).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank A. Sáez-Borderías and A. Arias for technical support. We also thank the Medical Oncology department, the Neurosurgery department and the Pathology department of the Vall d'Hebron Hospital for support. E.M.S. is supported by the Instituto Carlos III (CM09/143). I.B. and D.G.-D. were supported by the Red Temática de Investigación Cooperativa en Enfermedades Cardiovasculares (RECAVA, ISCIII). This work was supported by the European Research Council grant (ERC 205819), Instituto Carlos III grant FIS (PI070648), Ministry of Science and Innovation grant Consolider Ingenio 2010 program (CSD2009-00080) and the Asociación Española Contra el Cáncer (AECC) grant.

Author information

Authors and Affiliations

  1. Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, Barcelona, Spain

    Pieter J A Eichhorn, Laura Rodón, Alba Gonzàlez-Juncà, Magüi Gili, Claudia Aura, Aleix Prat, Isabel Cuartas, Jose Jimenez, José Baselga & Joan Seoane

  2. Division of Molecular Carcinogenesis and Centre for Biomedical Genetics, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    Annette Dirac & Réné Bernards

  3. Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron University Hospital, Barcelona, Spain

    Elena Martínez-Sáez, Ignasi Barba, Vicente Peg, David García-Dorado & Juan Sahuquillo

  4. Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA

    Aleix Prat

  5. Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain

    José Baselga & Joan Seoane

  6. Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA

    José Baselga

  7. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain

    Joan Seoane

Authors
  1. Pieter J A Eichhorn
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Laura Rodón
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alba Gonzàlez-Juncà
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Annette Dirac
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Magüi Gili
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Elena Martínez-Sáez
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Claudia Aura
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ignasi Barba
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Vicente Peg
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Aleix Prat
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Isabel Cuartas
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Jose Jimenez
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. David García-Dorado
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Juan Sahuquillo
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Réné Bernards
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. José Baselga
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Joan Seoane
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

P.J.A.E., L.R. and A.G.-J. performed all the experiments. A.D. and R.B. generated the DUB shRNA library. M.G. technically assisted in performing the in vitro experiments. E.M.-S., C.A., V.P. and J.J. performed the pathology analysis of the specimens. A.P. performed the bioinformatic analysis. I.B. and D.G.-D. performed the MRI analysis. I.C. performed the intracranial injections and technically assisted in the in vivo experiments. J. Sahuquillo was in charge of the human neurosurgical procedures. J.B. was in charge of the clinical analysis. J. Seoane designed and supervised the project and wrote the manuscript.

Corresponding author

Correspondence to Joan Seoane.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–5 (PDF 1126 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Eichhorn, P., Rodón, L., Gonzàlez-Juncà, A. et al. USP15 stabilizes TGF-β receptor I and promotes oncogenesis through the activation of TGF-β signaling in glioblastoma. Nat Med 18, 429–435 (2012). https://doi.org/10.1038/nm.2619

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.2619

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer