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Cystathionase mediates senescence evasion in melanocytes and melanoma cells

Oncogene volume 33, pages 771–782 (2014)Cite this article

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Abstract

The development of malignant melanoma is a highly complex process, which is still poorly understood. A majority of human melanomas are found to express a few oncogenic proteins, such as mutant RAS and BRAF variants. However, these oncogenes are also found in nevi, and it is now a well-accepted fact that their expression alone leads to senescence. This renders the understanding of senescence escape mechanisms an important point to understand tumor development. Here, we approached the question of senescence evasion by expressing the transcription factor v-myc myelocytomatosis viral oncogene homolog (c-MYC), which is known to act synergistically with many oncogenes, in melanocytes. We observed that MYC drives the evasion of reactive-oxygen stress-induced melanocyte senescence, caused by activated receptor tyrosine kinase signaling. Conversely, MIZ1, the growth suppressing interaction partner of MYC, is involved in mediating melanocyte senescence. Both, MYC overexpression and Miz1 knockdown led to a strong reduction of endogenous reactive-oxygen species (ROS), DNA damage and senescence. We identified the cystathionase (CTH) gene product as mediator of the ROS-related MYC and MIZ1 effects. Blocking CTH enzymatic activity in MYC-overexpressing and Miz1 knockdown cells increased intracellular stress and senescence. Importantly, pharmacological inhibition of CTH in human melanoma cells also reconstituted senescence in the majority of cell lines, and CTH knockdown reduced tumorigenic effects such as proliferation, H2O2 resistance and soft agar growth. Thus, we identified CTH as new MYC target gene with an important function in senescence evasion.

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Acknowledgements

We thank Dorothy Bennett, St George's, University of London (Wellcome Trust Functional Genomics Cell Bank) for providing the cell lines Hermes 3a and melan-a sut. This work was supported by the Deutsche Forschungsgesellschaft, Transregio 17 (‘RAS-dependent pathways in human cancer’). CL was supported by a grant of the German Excellence Initiative to the Graduate School of Life Sciences, University of Wurzburg.

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  1. C Leikam and A Hufnagel: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Physiological Chemistry I, Biocenter, University of Wurzburg, Wurzburg, Germany

    C Leikam, A Hufnagel, S Kneitz, M Schartl & S Meierjohann

  2. Department of Biochemistry and Molecular Biology, Biocenter, University of Wurzburg, Wurzburg, Germany

    S Walz & M Eilers

  3. Department of Pharmaceutical Biology, Julius-von-Sachs Institute for Biological Sciences, University of Wurzburg, Wurzburg, Germany

    A Fekete & M J Müller

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  1. C Leikam
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Leikam, C., Hufnagel, A., Walz, S. et al. Cystathionase mediates senescence evasion in melanocytes and melanoma cells. Oncogene 33, 771–782 (2014). https://doi.org/10.1038/onc.2012.641

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