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Atypical mechanism of NF-κB activation by TRE17/ubiquitin-specific protease 6 (USP6) oncogene and its requirement in tumorigenesis

Oncogene volume 31, pages 3525–3535 (2012)Cite this article

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Abstract

The NF-κB transcription factor has a central role in diverse processes, including inflammation, proliferation and cell survival, and its activity is dysregulated in diseases such as autoimmunity and cancer. We recently identified the TRE17/ubiquitin-specific protease 6 (USP6) oncogene as the first de-ubiquitinating enzyme to activate NF-κB. TRE17/USP6 is translocated and overexpressed in aneurysmal bone cyst (ABC), a pediatric tumor characterized by extensive bone degradation and inflammatory recruitment. In the current study, we explore the mechanism by which TRE17 induces activation of NF-κB, and find that it activates the classical NF-κB pathway through an atypical mechanism that does not involve IκB degradation. TRE17 co-precipitates with IκB kinase (IKK), and IKK activity is augmented in stable cell lines overexpressing TRE17, in a USP-dependent manner. Optimal activation of NF-κB by TRE17 requires both catalytic subunits of IKK, distinguishing its mechanism from the classical and non-canonical pathways, which require either IKKβ or IKKα, respectively. TRE17 stimulates phosphorylation of p65 at serine 536, a modification that has been associated with enhanced transcriptional activity and nuclear retention. Induction of S536 phosphorylation by TRE17 requires both IKKα and IKKβ, as well as the IKKγ/NEMO regulatory subunit of IKK. We further demonstrate that TRE17(long) is highly tumorigenic when overexpressed in NIH3T3 fibroblasts, and that inhibition of NF-κB significantly attenuates tumor formation. In summary, these studies uncover an unexpected signaling mechanism for activation of classical NF-κB by TRE17. They further reveal a critical role for NF-κB in TRE17-mediated tumorigenesis, and suggest that NF-κB inhibitors may function as effective therapeutic agents in the treatment of ABC.

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Acknowledgements

This work was supported by the National Institutes of Health Grant RO1 CA081415 (to MMC) and Grant P30 AS050950 (Penn Center for Musculoskeletal Disorders). This work was also supported by the National Service Research Award Grant F31CA126488 (to LMP).

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    L M Pringle, R Young, L Quick, D N Riquelme & M M Chou

  2. Department of Laboratory Medicine and Pathology, Mayo Clinic and Mayo Foundation, Rochester, MN, USA

    A M Oliveira

  3. Department of Animal Biology and the Mari Lowe Center for Comparative Oncology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, USA

    M J May

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  1. L M Pringle
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Correspondence to M M Chou.

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Pringle, L., Young, R., Quick, L. et al. Atypical mechanism of NF-κB activation by TRE17/ubiquitin-specific protease 6 (USP6) oncogene and its requirement in tumorigenesis. Oncogene 31, 3525–3535 (2012). https://doi.org/10.1038/onc.2011.520

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