DYRK1A is required for maintenance of cancer stemness, contributing to tumorigenic potential in oral/oropharyngeal squamous cell carcinoma

• Published in: Experimental cell research 2021-08, Vol.405 (1), p.112656, Article 112656
• Main Authors: Martin, Charlotte Ellen, Nguyen, Anthony, Kang, Mo K., Kim, Reuben H., Park, No-Hee, Shin, Ki-Hyuk
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; Animals; Apoptosis; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Cancer stem cells; Carcinogenesis - genetics; Carcinogenesis - metabolism; Carcinogenesis - pathology; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; CARCINOMAS; Cell Proliferation; Dyrk Kinases; DYRK1A; FGF2; FIBROBLASTS; Gene Expression Regulation, Neoplastic; GROWTH FACTORS; Humans; IN VIVO; INHIBITION; Mice; Mice, Nude; Mouth Neoplasms - genetics; Mouth Neoplasms - metabolism; Mouth Neoplasms - pathology; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Oropharyngeal Neoplasms - genetics; Oropharyngeal Neoplasms - metabolism; Oropharyngeal Neoplasms - pathology; OSCC; PHENOTYPE; PHOSPHORYLATION; PHOSPHOTRANSFERASES; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - metabolism; SPECIFICITY; STEM CELLS; Tumor Cells, Cultured; TYROSINE; Xenograft Model Antitumor Assays
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2021.112656

DYRK1A, one of the dual-specificity tyrosine phosphorylation-regulated kinases (DYRKs), plays an important role in various biological processes by regulating downstream targets via kinase-dependent and independent mechanisms. Here, we report a novel role of DYRK1A in maintaining tumor growth and stemness of oral/oropharyngeal squamous cell carcinoma (OSCC) cells. Deletion of DYRK1A from OSCC cells abrogated their in vivo tumorigenicity and self-renewal capacity, the key features of cancer stem-like cells (CSCs; also referred to as tumor-initiating cells). The DYRK1A deletion also induced the suppression of CSC populations and properties, such as migration ability and chemoresistance. Conversely, ectopic expression of DYRK1A in OSCC cells augmented their CSC phenotype. Among five DYRK members (DYRK1A, 1B, 2, 3, and 4), DYRK1A is the most dominantly expressed kinase, and its expression is upregulated in OSCC compared to normal oral epithelial cells. More importantly, DYRK1A was highly enriched in various CSC-enriched OSCC populations compared to their corresponding non-CSC populations, indicating its pivotal role in cancer progression and stemness. Further, our study revealed that fibroblast growth factor 2 (FGF2) is a key regulator in the DYRK1A-mediated CSC regulation. Functional studies demonstrated that the loss of DYRK1A inhibits CSC phenotype via reduction of FGF2. Overexpression of DYRK1A promotes CSC phenotype via upregulation of FGF2. Our study delineates a novel mechanism of cancer stemness regulation by DYRK1A-FGF2 axis in OSCC. Thus, inhibition of DYRK1A would lead to a potential novel therapeutic option for targeting CSCs in OSCC. •DYRK1A is essential to maintain cancer stemness in OSCC.•DYRK1A regulates cancer stemness via FGF2 expression.•Levels of DYRK1A and FGF2 expression are positively correlated in OSCC cells.•DYRK1A-FGF2 is a novel molecular axis regulating cancer stemness in OSCC.