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HAUSP deubiquitinates and stabilizes N-Myc in neuroblastoma

Nature Medicine volume 22, pages 1180–1186 (2016)Cite this article

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Abstract

The MYCN proto-oncogene is amplified in a number of advanced-stage human tumors, such as neuroblastomas. Similar to other members of the MYC family of oncoproteins, MYCN (also known as N-Myc) is a transcription factor, and its stability and activity are tightly controlled by ubiquitination-dependent proteasome degradation1,2,3,4. Although numerous studies have demonstrated that N-Myc is a driver of neuroblastoma tumorigenesis, therapies that directly suppress N-Myc activity in human tumors are limited. Here we have identified ubiquitin-specific protease 7 (USP7; also known as HAUSP)5,6,7 as a regulator of N-Myc function in neuroblastoma. HAUSP interacts with N-Myc, and HAUSP expression induces deubiquitination and subsequent stabilization of N-Myc. Conversely, RNA interference (RNAi)-mediated knockdown of USP7 in neuroblastoma cancer cell lines, or genetic ablation of Usp7 in the mouse brain, destabilizes N-Myc, which leads to inhibition of N-Myc function. Notably, HAUSP is more abundant in patients with neuroblastoma who have poorer prognosis, and HAUSP expression substantially correlates with N-Myc transcriptional activity. Furthermore, small-molecule inhibitors of HAUSP's deubiquitinase activity markedly suppress the growth of MYCN-amplified human neuroblastoma cell lines in xenograft mouse models. Taken together, our findings demonstrate a crucial role of HAUSP in regulating N-Myc function in vivo and suggest that HAUSP inhibition is a potential therapy for MYCN-amplified tumors.

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Figure 1: HAUSP affects and directly interacts with N-Myc both in vitro and in vivo.
Figure 2: HAUSP regulates N-Myc through deubiquitination.
Figure 3: Pharmacologically blocking HAUSP-mediated deubiquitination in neuroblastoma cells.
Figure 4: The role of HAUSP on the pathogenesis of neuroblastomas.

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Acknowledgements

The authors would like to thank J. Maris (Children's Hospital of Philadelphia) for providing cell lines. This work was supported by the National Cancer Institute, US National Institutes of Health (NIH) (grant no. 5R01CA193890, 5RO1CA190477, 5RO1CA085533 and 2P01CA080058; all to W.G.) and was partially supported by the NIH cancer biology training grant T32-CA09503 (O.T.). The content of this paper is solely the responsibility of the authors and does not necessarily represent the official views of the US National Institutes of Health.

Author information

Authors and Affiliations

  1. Institute for Cancer Genetics, College of Physicians and Surgeons, Columbia University, New York, New York, USA

    Omid Tavana, Dawei Li, Chao Dai, Gonzalo Lopez, Ning Kon, Andrea Califano & Wei Gu

  2. Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, New York, USA

    Omid Tavana, Dawei Li, Chao Dai, Gonzalo Lopez, Debarshi Banerjee, Ning Kon, Andrea Califano, Darrell J Yamashiro & Wei Gu

  3. Department of Systems Biology, College of Physicians and Surgeons, Columbia University, New York, New York, USA

    Gonzalo Lopez & Andrea Califano

  4. Center for Computational Biology and Bioinformatics, College of Physicians and Surgeons, Columbia University, New York, New York, USA

    Gonzalo Lopez & Andrea Califano

  5. Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, New York, USA

    Debarshi Banerjee & Darrell J Yamashiro

  6. Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, Nanjing, China

    Chao Chen & Hongbin Sun

  7. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China

    Chao Chen & Hongbin Sun

  8. Department of Biomedical Informatics, Biochemistry and Molecular Biophysics, College of Physicians and Surgeons, Columbia University, New York, New York, USA

    Andrea Califano

  9. Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, New York, USA

    Wei Gu

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Contributions

The whole project was conceived and designed by O.T. and W.G.; experiments were performed mainly by O.T., D.L. and C.D.; bioinformatic analysis was performed by G.L. and A.C.; and some of the experiments were performed with help from D.B., N.K., C.C., H.S. and D.J.Y. The paper was written by O.T. and W.G.

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Correspondence to Wei Gu.

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Tavana, O., Li, D., Dai, C. et al. HAUSP deubiquitinates and stabilizes N-Myc in neuroblastoma. Nat Med 22, 1180–1186 (2016). https://doi.org/10.1038/nm.4180

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