The dual fate of DYRK2 in cancer: balancing the light and dark side of tumorigenesis

Dual-specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2) is emerging as a pivotal player in cancer biology due to its pleiotropic cellular roles, functioning either as a tumor suppressor or an oncogene in a tissue- and genotype-dependent manner. DYRK2 regulates critical processes including cell cycle progression, DNA damage response, and stress signaling. As a tumor suppressor, DYRK2 facilitates the degradation of oncogenic proteins (e.g., c-Myc, SNAIL, TERT) and enhances apoptosis via p53 activation. Loss of DYRK2 has been associated with poor prognosis and chemoresistance in cancers such as colorectal, breast, and liver. Conversely, DYRK2 overexpression in certain tumors, including triple-negative breast cancer and ovarian carcinoma, supports oncogenic roles by enhancing proteasome function, promoting epithelial-mesenchymal transition, and contributing to therapy resistance. This functional dichotomy is modulated by post-translational modifications, microenvironmental stress, epigenetic regulation, subcellular localization, and interaction with protein complexes, underscoring the complexity of DYRK2 regulation. Therapeutically, DYRK2 represents a promising but context-sensitive target, with inhibitors showing efficacy in preclinical models of proteasome-addicted cancers, although precise biomarkers and cancer subtype stratification remain critical. Future directions include refining in vivo models and delineating the role of DYRK2 in cancer stem cell dynamics and immune modulation, emphasizing that understanding its context-dependent activity is essential to exploit its full therapeutic potential in oncology.