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Cytoplasmic DRAK1 overexpressed in head and neck cancers inhibits TGF-β1 tumor suppressor activity by binding to Smad3 to interrupt its complex formation with Smad4

Oncogene volume 34, pages 5037–5045 (2015)Cite this article

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Abstract

Head and neck squamous cell carcinoma (HNSCC) is an extremely aggressive cancer with a poor prognosis and low patient survival. Because chemotherapy for advanced HNSCC is often ineffective, discovering new therapeutic targets that are important for HNSCC development and progression and elucidating their molecular mechanisms are required. In the present study, we describe the role of DRAK1 (death-associated protein kinase-related apoptosis-inducing kinase 1) as a novel negative regulator of the transforming growth factor-β (TGF-β) tumor suppressor signaling pathway for the first time in human HNSCC cells. DRAK1 was significantly overexpressed in primary human HNSCCs and in HNSCC cell lines. Through gain- and loss-of-function experiments, we demonstrated that the DRAK1 expression level regulated TGF-β1-induced transcriptional activity and expression of the tumor suppressor gene p21Waf1/Cip1. DRAK1 depletion enhanced TGF-β1-induced growth inhibition in vitro and suppressed tumorigenicity in xenograft models in vivo. Mechanistically, DRAK1 was predominantly localized in the cytoplasm and bound to Smad3, thereby interrupting Smad3/Smad4 complex formation, which is the core process for the induction of tumor suppressor genes by TGF-β1. Thus, our findings suggest that cytoplasmic DRAK1 increases tumorigenic potential through inhibition of TGF-β1-mediated tumor suppressor activity in HNSCC cells and may be a potential therapeutic target for HNSCCs.

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Acknowledgements

This research was supported by the Bio-Synergy Research Project (NRF-2012M3A9C4048735 to S-JK), Bio & Medical Technology Development Program (NRF-2009-0081756 to S-JK) and Basic Science Research Program (NRF-2014R1A1A1005186 to K-MY), through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning.

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Author notes

  1. Y Park and W Kim: These authors contributed equally to this work.

Authors and Affiliations

  1. CHA Cancer Institute,

    Y Park, W Kim, J-M Lee, J Park, J K Cho, K Pang, J Lee, D Kim, K-M Yang & S-J Kim

  2. CHA University, Seoul, Korea

    Y Park, W Kim, J-M Lee, J Park, J K Cho, K Pang, J Lee, D Kim, K-M Yang & S-J Kim

  3. College of Medicine,

    W Kim

  4. CHA University, Seoul, Korea

    W Kim

  5. College of Pharmacy,

    J-M Lee & J Park

  6. CHA University, Seoul, Korea

    J-M Lee & J Park

  7. Department of Biomedical Science, CHA University, Seoul, Korea

    J K Cho, K Pang, J Lee & S-J Kim

  8. Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea

    S-W Park

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Correspondence to K-M Yang or S-J Kim.

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Park, Y., Kim, W., Lee, JM. et al. Cytoplasmic DRAK1 overexpressed in head and neck cancers inhibits TGF-β1 tumor suppressor activity by binding to Smad3 to interrupt its complex formation with Smad4. Oncogene 34, 5037–5045 (2015). https://doi.org/10.1038/onc.2014.423

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