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WIP1 phosphatase modulates the Hedgehog signaling by enhancing GLI1 function

Oncogene volume 32, pages 4737–4747 (2013)Cite this article

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Abstract

The Hedgehog-GLI (HH-GLI) signaling plays a critical role in controlling growth and tissue patterning during embryogenesis and is implicated in a variety of human malignancies, including those of the skin. Phosphorylation events have been shown to regulate the activity of the GLI transcription factors, the final effectors of the HH-GLI signaling pathway. Here, we show that WIP1 (or PPM1D), an oncogenic phosphatase amplified/overexpressed in several types of human cancer, is a positive modulator of the HH signaling. Mechanistically, WIP1 enhances the function of GLI1 by increasing its transcriptional activity, nuclear localization and protein stability, but not of GLI2 nor GLI3. We also find that WIP1 and GLI1 are in a complex. Modulation of the transcriptional activity of GLI1 by WIP1 depends on the latter’s phosphatase activity and, remarkably, does not require p53, a known WIP1 target. Functionally, we find that WIP1 is required for melanoma and breast cancer cell proliferation and self-renewal in vitro and melanoma xenograft growth induced by activation of the HH signaling. Pharmacological blockade of the HH pathway with the SMOOTHENED antagonist cyclopamine acts synergistically with inhibition of WIP1 in reducing growth of melanoma and breast cancer cells in vitro. Overall, our data uncover a role for WIP1 in modulating the activity of GLI1 and in sustaining cancer cell growth and cancer stem cell self-renewal induced by activation of the HH pathway. These findings open a novel therapeutic approach for human melanomas and, possibly, other cancer types expressing WIP1 and with activated HH pathway.

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Acknowledgements

We thank G Del Sal, A Ruiz i Altaba, L Luzzatto for helpful comments on the paper and discussion. We are grateful to G Del Sal (Laboratorio Nazionale CIB, Padriciano, Italy) for HCT116 p53wt and p53ko cells, A Ruiz i Altaba (University of Geneva, Geneva, Switzerland), H Sasaki (NCCRI, Tokyo, Japan), RH Medema (University of Utrecht, Utrecht, The Netherlands) for plasmids, G Gerlini (S Maria Annunziata Hospital, Florence, Italy) for help in obtaining samples, E Rovida (University of Florence, Florence, Italy) for assistance with confocal microscopy. This work was supported by grants from Associazione Italiana per la Ricerca sul Cancro (AIRC, 9566), Regional Health Research Program 2009 and Fondazione Cassa di Risparmio di Firenze to BS. SP was supported by AIRC fellowship.

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  1. Laboratory of Tumor Cell Biology, Core Research Laboratory—Istituto Toscano Tumori (CRL-ITT), Florence, Italy

    S Pandolfi, V Montagnani, J Y Penachioni, M C Vinci & B Stecca

  2. Department of Pediatrics, Immunology Unit, Anna Meyer Children's Hospital, Florence, Italy

    B Olivito

  3. Plastic Surgery Unit, S.M. Annunziata Hospital—Regional Melanoma Referral Center, Istituto Toscano Tumori, Florence, Italy

    L Borgognoni

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  1. S Pandolfi
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Correspondence to B Stecca.

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Pandolfi, S., Montagnani, V., Penachioni, J. et al. WIP1 phosphatase modulates the Hedgehog signaling by enhancing GLI1 function. Oncogene 32, 4737–4747 (2013). https://doi.org/10.1038/onc.2012.502

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