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C-MYC overexpression is required for continuous suppression of oncogene-induced senescence in melanoma cells

Abstract

Malignant melanomas often harbor activating mutations in BRAF (V600E) or, less frequently, in NRAS (Q61R). Intriguingly, the same mutations have been detected at higher incidences in benign nevi, which are largely composed of senescent melanocytes. Overexpression of BRAFV600E or NRASQ61R in human melanocytes in vitro has been shown to induce senescence, although via different mechanisms. How oncogene-induced senescence is overcome during melanoma progression remains unclear. Here, we report that in the majority of analysed BRAFV600E- or NRASQ61R-expressing melanoma cells, C-MYC depletion induced different yet overlapping sets of senescence phenotypes that are characteristic of normal melanocytes undergoing senescence due to overexpression of BRAFV600E or NRASQ61R, respectively. These senescence phenotypes were p16INK4A- or p53-independent, however, several of them were suppressed by genetic or pharmacological inhibition of BRAFV600E or phosphoinositide 3-kinase pathways, including rapamycin-mediated inhibition of mTOR-raptor in NRASQ61R-expressing melanoma cells. Reciprocally, overexpression of C-MYC in normal melanocytes suppressed BRAFV600E-induced senescence more efficiently than NRASQ61R-induced senescence, which agrees with the generally higher rates of activating mutations in BRAF than NRAS gene in human cutaneous melanomas. Our data suggest that one of the major functions of C-MYC overexpression in melanoma progression is to continuous suppress BRAFV600E- or NRASQ61R-dependent senescence programs.

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Acknowledgements

We are grateful to Michelle Vinco for assistance with the human tissue work. This work was supported by Grants NIH R01 CA120244 (MAN), CA107237 (MSS), and, in part, by the University of Michigan's Cancer Center Support Grant (NIH 5 P30 CA46592). MAN is a Melanoma Research Foundation Scholar.

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Correspondence to M A Nikiforov.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Zhuang, D., Mannava, S., Grachtchouk, V. et al. C-MYC overexpression is required for continuous suppression of oncogene-induced senescence in melanoma cells. Oncogene 27, 6623–6634 (2008). https://doi.org/10.1038/onc.2008.258

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