title: 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.
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 p21(Waf1/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.
authors.affiliation: CHA Cancer Institute, CHA University, Seoul, Korea.
authors.forename: Y
authors.initials: Y
authors.lastname: Park
authors.affiliation: CHA Cancer Institute, CHA University, Seoul, Korea.|College of Medicine, CHA University, Seoul, Korea.
authors.forename: W
authors.initials: W
authors.lastname: Kim
authors.affiliation: CHA Cancer Institute, CHA University, Seoul, Korea.|College of Pharmacy, CHA University, Seoul, Korea.
authors.forename: J-M
authors.initials: JM
authors.lastname: Lee
authors.affiliation: CHA Cancer Institute, CHA University, Seoul, Korea.|College of Pharmacy, CHA University, Seoul, Korea.
authors.forename: J
authors.initials: J
authors.lastname: Park
authors.affiliation: CHA Cancer Institute, CHA University, Seoul, Korea.|Department of Biomedical Science, CHA University, Seoul, Korea.
authors.forename: J K
authors.initials: JK
authors.lastname: Cho
authors.affiliation: CHA Cancer Institute, CHA University, Seoul, Korea.|Department of Biomedical Science, CHA University, Seoul, Korea.
authors.forename: K
authors.initials: K
authors.lastname: Pang
authors.affiliation: CHA Cancer Institute, CHA University, Seoul, Korea.|Department of Biomedical Science, CHA University, Seoul, Korea.
authors.forename: J
authors.initials: J
authors.lastname: Lee
authors.affiliation: CHA Cancer Institute, CHA University, Seoul, Korea.
authors.forename: D
authors.initials: D
authors.lastname: Kim
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: S-W
authors.initials: SW
authors.lastname: Park
authors.affiliation: CHA Cancer Institute, CHA University, Seoul, Korea.
authors.forename: K-M
authors.initials: KM
authors.lastname: Yang
authors.affiliation: CHA Cancer Institute, CHA University, Seoul, Korea.|Department of Biomedical Science, CHA University, Seoul, Korea.
authors.forename: S-J
authors.initials: SJ
authors.lastname: Kim
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000378:metabolism*; D006258:Head and Neck Neoplasms / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D051900:Smad3 Protein / Q000378:metabolism*; D051901:Smad4 Protein / Q000378:metabolism*; D015533:Transcriptional Activation; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology
chemical_list: D051017:Apoptosis Regulatory Proteins; C497790:SMAD3 protein, human; C497796:SMAD4 protein, human; D051900:Smad3 Protein; D051901:Smad4 Protein; D053773:Transforming Growth Factor beta1; D017346:Protein Serine-Threonine Kinases; C115488:STK17A protein, human