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PP2A-B56α controls oncogene-induced senescence in normal and tumor human melanocytic cells

Oncogene volume 31, pages 1484–1492 (2012)Cite this article

Abstract

Oncoprotein C-MYC is overexpressed in human metastatic melanomas and melanoma-derived cells where it is required for the suppression of oncogene-induced senescence (OIS). The genetic events that maintain high levels of C-MYC in melanoma cells and their role in OIS are unknown. Here we report that C-MYC in cells from several randomly chosen melanoma lines was upregulated at the protein level, and largely because of the increased protein stability. Of all known regulators of C-MYC stability, levels of B56α subunit of the PP2A tumor suppressor complex were substantially suppressed in all human melanoma cells compared with normal melanocytes. Accordingly, immunohistochemical analysis revealed that the lowest and the highest amounts of PP2A-B56α were predominantly detected in metastatic melanoma tissues and in primary melanomas from patients with good clinical outcome, respectively. Importantly, PP2A-B56α overexpression suppressed C-MYC in melanoma cells and induced OIS, whereas depletion of PP2A-B56α in normal human melanocytes upregulated C-MYC protein levels and suppressed BRAFV600E- and, less efficiently, NRASQ61R-induced senescence. Our data reveal a mechanism of C-MYC overexpression in melanoma cells and identify a functional role for PP2A-B56α in OIS of melanocytic cells.

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Acknowledgements

We are grateful to Dr Catherine Burkhart (Cleveland Biolabs) and Dr Shoshanna Zucker (Roswell Park Cancer Institute) for critical reading of the manuscript, Ms Carina Fung (University of Sydney) for the experimental help. This work was supported by the NIH R01 CA120244 and ACS RSG-10-121-01 grants to MAN. The work of JCM was supported in part by the NIH 5P30CA016056-34 grant.

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Authors and Affiliations

  1. Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA

    S Mannava, J A Wawrzyniak, E E Fink, D Zhuang & M A Nikiforov

  2. Department of Pathology, Roswell Park Cancer Institute, Buffalo, NY, USA

    A R Omilian & C D Morrison

  3. Department of Biostatistics, Roswell Park Cancer Institute, Buffalo, NY, USA

    J C Miecznikowski

  4. Department of Cancer Prevention and Population Sciences, Roswell Park Cancer Institute, Buffalo, NY, USA

    J R Marshall

  5. Molecular Pathology Programme, Spanish National Cancer Research Center, Madrid, Spain

    M S Soengas

  6. Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA

    R C Sears

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Correspondence to M A Nikiforov.

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Mannava, S., Omilian, A., Wawrzyniak, J. et al. PP2A-B56α controls oncogene-induced senescence in normal and tumor human melanocytic cells. Oncogene 31, 1484–1492 (2012). https://doi.org/10.1038/onc.2011.339

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