Abstract
Oncogene-induced senescence (OIS) is a critical tumor-suppressor mechanism, which prevents hyper-proliferation and transformation of cells. c-Myc promotes OIS through the transcriptional activation of p14ARF followed by p53 activation. Although the oncogene-mediated transcriptional regulation of p14ARF has been well addressed, the post-translational modification of p14ARF regulated by oncogenic stress has yet to be investigated. Here, we found that c-Myc increased p14ARF protein stability by inducing the transcription of ubiquitin-specific protease 10 (USP10). USP10, in turn, mediated the deubiquitination of p14ARF, preventing its proteasome-dependent degradation. USP10-null mouse embryonic fibroblasts and human primary cells depleted of USP10 bypassed c-Myc-induced senescence via the destabilization of p14ARF, and these cells displayed accelerated hyper-proliferation and transformation. Clinically the c-Myc-USP10-p14ARF axis was disrupted in non-small cell lung cancer patients, resulting in significantly worse overall survival. Our studies indicate that USP10 induced by c-Myc has a crucial role in OIS by maintaining the stability of key tumor suppressor p14ARF.
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Acknowledgements
This work was supported by grants from the Basic Science Research Program of the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (2014R1A1A1002589) and Creative Research Initiative Program of NRF (2015R1A3A2066581) funded by the Ministry of Science, ICT.
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JS and AK conceived and designed the projects and wrote the manuscript. AK and SYH performed the experiments. MSL, SYK and HWL provided technical and material support. CHC, HC, JSS, KH, SMH, and JYC performed the clinical analysis.
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These authors contributed equally: Aram Ko, Su Yeon Han.
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Ko, A., Han, S.Y., Choi, C.H. et al. Oncogene-induced senescence mediated by c-Myc requires USP10 dependent deubiquitination and stabilization of p14ARF. Cell Death Differ 25, 1050–1062 (2018). https://doi.org/10.1038/s41418-018-0072-0
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DOI: https://doi.org/10.1038/s41418-018-0072-0
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