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ΔNp63α regulates Erk signaling via MKP3 to inhibit cancer metastasis

Oncogene volume 33, pages 212–224 (2014)Cite this article

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Abstract

Reduced expression of the p53 family member p63 has been suggested to play a causative role in cancer metastasis. Here, we show that ΔNp63α, the predominant p63 isoform, plays a major role in regulation of cell migration, invasion and cancer metastasis. We identified mitogen-activated protein (MAP) kinase phosphatase 3 (MKP3) as a downstream target of ΔNp63α that is required for mediating these effects. We show that ΔNp63α regulates extracellular signal-regulated protein kinases 1 and 2 (Erk1/2) activity via MKP3 in both cancer and non-transformed cells. We further show that exogenous ΔNp63α inhibits cell invasion and is dependent on MKP3 upregulation for repression. Conversely, endogenous pan-p63 ablation results in increased cell migration and invasion, which can be reverted by reintroducing the ΔNp63α isoform alone, but not by other isoforms. Interestingly, these effects require Erk2, but not Erk1 expression, and can be rescued by enforced MKP3 expression. Moreover, MKP3 expression is reduced in invasive cancers, and reduced p63 expression increases metastatic frequency in vivo. Taken together, these results suggest an important role for ΔNp63α in preventing cancer metastasis by inhibition of Erk2 signaling via MKP3.

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Acknowledgements

We thank Dr Frank McKeon (Harvard Medical School, Boston, MA, USA) for providing the myc-tagged murine pcDNA3-ΔNp63α, pcDNA3-ΔNp63γ, pcDNA3-TAp63α and pcDNA3-TAp63γ expression plasmids, and Dr Tyler Jacks (Massachusetts Institute of Technology, Cambridge, MA, USA) for providing a plasmid encoding shRNA against human MKP3. We also thank Dr Xixi Cao (Baylor College of Medicine) for help with Oncomine bioinformatics analysis. This work was supported by NIH grants (CA79804 and GM70017) and by the National Key Basic Research Program (973 Program) of China (2012CB910700) to Z-XJX, and United States Department of Defense Congressionally Directed Medical Research Programs grant (W81XWH-10-1-0161) to JB.

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  1. Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA

    J Bergholz, J Wu, L Meng, E M Walsh, A Rai, M Y Sherman & Z-X Jim Xiao

  2. Center of Growth, Metabolism and Aging, College of Life Sciences and State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China

    J Bergholz, Y Zhang & Z-X Jim Xiao

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  1. J Bergholz
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Bergholz, J., Zhang, Y., Wu, J. et al. ΔNp63α regulates Erk signaling via MKP3 to inhibit cancer metastasis. Oncogene 33, 212–224 (2014). https://doi.org/10.1038/onc.2012.564

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