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Oncogenic suppression of PHLPP1 in human melanoma

Oncogene volume 33, pages 4756–4766 (2014)Cite this article

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Abstract

Akt is constitutively activated in up to 70% of human melanomas and has an important role in the pathogenesis of the disease. However, little is known about protein phosphatases that dephosphorylate and thereby inactivate it in melanoma cells. Here we report that suppression of pleckstrin homology domain and leucine-rich repeat Ser/Thr protein phosphatase 1 (PHLPP1) by DNA methylation promotes Akt activation and has an oncogenic role in melanoma. While it is commonly downregulated, overexpression of PHLPP1 reduces Akt activation and inhibits melanoma cell proliferation in vitro, and retards melanoma growth in a xenograft model. In contrast, knockdown of PHLPP1 increases Akt activation, enhances melanoma cell and melanocyte proliferation, and results in anchorage-independent growth of melanocytes. Suppression of PHLPP1 involves blockade of binding of the transcription factor Sp1 to the PHLPP1 promoter. Collectively, these results suggest that suppression of PHLPP1 by DNA methylation contributes to melanoma development and progression.

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Acknowledgements

This work was supported by the National Health and Medical Research Council (NHMRC), the Cancer Council NSW, Cancer Institute NSW and Hunter Medical Research Institute, Australia; and National Natural Science Foundation of China. XDZ is supported by senior research fellowships of NHMRC. RAS is supported by the Cancer Institute NSW Fellowship Program. We thank Dr Tianyan Gao (Markey Cancer Center, University of Kentucky) for the pcDNA3-PHLPP1-HA constructs.

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  1. L Dong and L Jin: These authors contributed equally to this work.

Authors and Affiliations

  1. School of Medicine and Public Health, The University of Newcastle, Newcastle, NSW, Australia

    L Dong, L Jin, H-Y Tseng, X G Yan, C C Jiang & X D Zhang

  2. Department of Molecular Biology, Shanxi Cancer Hospital and Institute, Affiliated Hospital of Shanxi Medical University, Taiyuan, China

    C Y Wang & S T Guo

  3. Melanoma Institute Australia, Sydney, NSW, Australia

    J S Wilmott, B Yosufi & R A Scolyer

  4. Discipline of Pathology, The University of Sydney, Sydney, NSW, Australia

    J S Wilmott & R A Scolyer

  5. Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, NSW, Australia

    R A Scolyer

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Dong, L., Jin, L., Tseng, HY. et al. Oncogenic suppression of PHLPP1 in human melanoma. Oncogene 33, 4756–4766 (2014). https://doi.org/10.1038/onc.2013.420

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