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USP8 suppresses death receptor-mediated apoptosis by enhancing FLIPL stability

Oncogene volume 36, pages 458–470 (2017)Cite this article

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Abstract

FLICE-like inhibitory protein (FLIP) is a critical regulator of death receptor-mediated apoptosis. Here, we found ubiquitin-specific peptidase 8 (USP8) to be a novel deubiquitylase of the long isoform of FLIP (FLIPL). USP8 directly deubiquitylates and stabilizes FLIPL, but not the short isoform. USP8 depletion induces FLIPL destabilization, promoting anti-Fas-, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)- and tumor necrosis factor alpha-induced extrinsic apoptosis by facilitating death-inducing signaling complex or TNFR1 complex II formation, which results in the activation of caspase-8 and caspase-3. USP8 mRNA levels are elevated in melanoma and cervical cancers, and the protein levels of USP8 and FLIPL are positively correlated in these cancer cell lines. Xenograft analyses using ME-180 cervical cancer cells showed that USP8 depletion attenuated tumor growth upon TRAIL injection. Taken together, our data indicate that USP8 functions as a novel deubiquitylase of FLIPL and inhibits extrinsic apoptosis by stabilizing FLIPL.

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Acknowledgements

This work was supported by a grant from the National Research Foundation of Korea (NRF), funded by the Ministry of Science, ICT and Future Planning (NRF-2015R1A3A2066581) (to J Song) and by the Ministry of Education (2012R1A6A3A04040105) (to E-WL).

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Authors and Affiliations

  1. Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea

    M Jeong, E-W Lee, D Seong, J Seo, J-H Kim & J Song

  2. Inflammation Research Center, VIB, Zwijnaarde-Ghent, Belgium

    S Grootjans & P Vandenabeele

  3. Department of Biomedical Molecular Biology, Ghent University, Zwijnaarde-Ghent, Belgium

    S Grootjans & P Vandenabeele

  4. Division of Cancer Biology, Cancer Cell and Molecular Biology Branch, Research Institute, National Cancer Center, Goyang, Korea

    S-Y Kim

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Jeong, M., Lee, EW., Seong, D. et al. USP8 suppresses death receptor-mediated apoptosis by enhancing FLIPL stability. Oncogene 36, 458–470 (2017). https://doi.org/10.1038/onc.2016.215

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