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DDIAS suppresses TRAIL-mediated apoptosis by inhibiting DISC formation and destabilizing caspase-8 in cancer cells

Oncogenevolume 37pages12511262 (2018) | Download Citation

Abstract

DNA damage-induced apoptosis suppressor (DDIAS) has an anti-apoptotic function during DNA damage in lung cancer. However, the anti-apoptotic mechanism of DDIAS in cancer cells under other conditions has not been reported. We report here that DDIAS protects cancer cells from tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by two distinct mechanisms in non-small cell lung cancer (NSCLC) and hepatocellular carcinoma (HCC) cells. DDIAS depletion sensitized NSCLC and HCC cells to TRAIL-mediated apoptosis, an effect that was abrogated by pharmacological or genetic inhibition of caspase-8 and was independent of caspase-9, p53, or mitogen-activated protein kinase signaling. Interestingly, we found that the N terminus of DDIAS interacted with the death effector domain of Fas-associated protein death domain (FADD) and prevented its recruitment to the death-inducing signaling complex (DISC), thereby blocking caspase-8 activation. DDIAS knockdown also suppressed epidermal growth factor-induced phosphorylation of p90 ribosomal S6 kinase (RSK) 2 and stabilized caspase-8 by preventing its ubiquitination and proteasomal degradation. This effect was abolished by RSK2 overexpression. Taken together, DDIAS has dual functions in inhibiting DISC formation as well as in destabilizing caspase-8, thereby suppressing TRAIL-mediated apoptosis of cancer cells. Thus, we suggest that DDIAS can serve as an effective therapeutic target in the treatment of NSCLC and HCC.

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Additional information

Joo-Young Im and Bo-Kyung Kim contributed equally to this work.

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Acknowledgments

This work was supported by the KRIBB Initiative Program (KGM4751713), National Research Foundation (NRF; 2017R1A2B2011936 and 2017M3A9F9030565), and Health Technology R&D (HI13C2162).

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    Affiliations

    1. Personalized Genomic Medicine Research Center, KRIBB, Daejeon, Korea

      • Joo-Young Im
      • , Bo-Kyung Kim
      • , Ji-Young Lee
      • , Seung-Ho Park
      •  & Misun Won
    2. Metabolic Regulation Research Center, KRIBB, Daejeon, Korea

      • Hyun Seung Ban
    3. ST Pharm. Co., LTD, Sihwa Industrial Complex 1, Kyunggido, Korea

      • Kyeong Eun Jung
    4. Department of Functional Genomics, KRIBB School of Biotechnology, Korea University of Science and Technology(UST), 217 Gajeong-ro, Yuseong-gu, Daejeon, Korea

      • Misun Won

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    Correspondence to Misun Won.

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    https://doi.org/10.1038/s41388-017-0025-y