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WIP1 modulates responsiveness to Sonic Hedgehog signaling in neuronal precursor cells and medulloblastoma

Oncogene volume 35, pages 5552–5564 (2016)Cite this article

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Abstract

High-level amplification of the protein phosphatase PPM1D (WIP1) is present in a subset of medulloblastomas (MBs) that have an expression profile consistent with active Sonic Hedgehog (SHH) signaling. We found that WIP1 overexpression increased expression of Shh target genes and cell proliferation in response to Shh stimulation in NIH3T3 and cerebellar granule neuron precursor cells in a p53-independent manner. Thus, we developed a mouse in which WIP1 is expressed in the developing brain under control of the Neurod2 promoter (ND2:WIP1). The external granule layer (EGL) in early postnatal ND2:WIP1 mice exhibited increased proliferation and expression of Shh downstream targets. MB incidence increased and survival decreased when ND2:WIP1 mice were crossed with an Shh-activated MB mouse model. Conversely, Wip1 knockout significantly suppressed MB formation in two independent mouse models of Shh-activated MB. Furthermore, Wip1 knockdown or treatment with a WIP1 inhibitor suppressed the effects of Shh stimulation and potentiated the growth inhibitory effects of SHH pathway-inhibiting drugs in Shh-activated MB cells in vitro. This suggests an important cross-talk between SHH and WIP1 pathways that accelerates tumorigenesis and supports WIP1 inhibition as a potential treatment strategy for MB.

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Acknowledgements

We acknowledge Drs James Olson and Xiongbin Lu for providing mice and expression constructs, and Dr Oskar Laur in the Emory University CCCF for plasmid construction. This work was supported by the NIH (1R01CA172392, RCC; CA159859, MDT), St Baldrick’s Foundation (RCC), CURE Childhood Cancer Foundation (RCC) and the Dr Mildred-Scheel Foundation (MR).

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Authors and Affiliations

  1. Department of Pediatrics, Aflac Cancer and Blood Disorders Center, , Atlanta, GA, USA

    J Wen, J Lee, A Malhotra, A R Arnold, M C Buss, B D Brown, C Maier, A M Kenney & R C Castellino

  2. Winship Cancer Institute, and the Emory University School of Medicine, Atlanta, GA, USA

    R Nahta, A M Kenney & R C Castellino

  3. Department of Pharmacology, , Atlanta, GA, USA

    R Nahta

  4. Division of Neurosurgery, Arthur and Sonia Labatt Brain Tumour Research Center, and Program in Developmental and Stem Cell Biology, Toronto, Ontario, Canada

    M Remke & M D Taylor

  5. Division of Haematology/Oncology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada

    V Ramaswamy

  6. Children’s Healthcare of Atlanta, , Atlanta, GA, USA

    R C Castellino

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  1. J Wen
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Correspondence to R C Castellino.

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Wen, J., Lee, J., Malhotra, A. et al. WIP1 modulates responsiveness to Sonic Hedgehog signaling in neuronal precursor cells and medulloblastoma. Oncogene 35, 5552–5564 (2016). https://doi.org/10.1038/onc.2016.96

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