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

• Type of Material: Article
• Authors: Jing Wen, AFLAC; Juhyun Lee, AFLAC; Anshu Malhotra, Emory University; Rita Nahta, Emory University; Amanda R. Arnold, AFLAC; Meghan C. Buss, AFLAC; Briana D. Brown, AFLAC; Caroline Maier, AFLAC; Anna Kenney, Emory University; Marc Remke, Arthur and Sonia Labatt Brain Tumour Research Centre; Vijay Ramaswamy, Hospital for Sick Children University of Toronto; Michael D. Taylor, Arthur and Sonia Labatt Brain Tumour Research Centre; Robert Castellino, Emory University
• Language: English
• Date: 2016-10-20
• Publisher: Nature Publishing Group: Open Access Hybrid Model Option B
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2016 Macmillan Publishers Limited, part of Springer Nature.
• Final Published Version (URL): http://dx.doi.org/10.1038/onc.2016.96
• Title of Journal or Parent Work: Oncogene
• ISSN: 0950-9232
• Volume: 35
• Issue: 42
• Start Page: 5553
• End Page: 5564
• Grant/Funding Information: Work was supported by the NIH (1R01CA172392, R.C.C.; CA159859, M.D. Taylor), St. Baldrick’s Foundation (R.C.C.), CURE Childhood Cancer Foundation (R.C.C.), and the Dr. Mildred-Scheel Foundation (M.R.).
• Keywords: WIP1; p53; PPM1D; Hedgehog; medulloblastoma
• Research Categories: Biology, Molecular; Health Sciences, Oncology; Biology, Neuroscience

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.