Over the last decade, the CMGC-kinase, DYRK2, has been reported as a tumour-suppressor across various cancers triggering major anti-tumour and pro-apoptotic signals in breast, colon, liver, ovary, brain, and lung cancers, while lower DYRK2 expression apparently correlated with poorer prognosis in patients. Contrary to this, various medicinal chemistry studies reported robust anti-proliferative properties of DYRK2 inhibitors while unbiased ‘omics’ and GWAS based studies identified DYRK2 as a highly overexpressed kinase in various patient tumour samples. A major paradigm shift occurred in the last four years when DYRK2 was found to regulate proteostasis in cancer via a two-pronged mechanism. DYRK2 phosphorylated and activated the 26S proteasome to enhance degradation of mis-folded/tumour-suppressor proteins while also promoting the nuclear stability and transcriptional activity of its substrate, heat-shock factor 1 (HSF1) triggering protein folding. Together, DYRK2 regulates proteostasis and promotes pro-tumorigenic survival for specific cancers. Indeed, potent and selective small molecule inhibitors of DYRK2 exhibit in vitro and in vivo anti-tumour activity in triple negative breast cancer (TNBC) and myeloma models. Thus, with conflicting and contradictory reports across different cancers, the overarching role of DYRK2 remains enigmatic. Specific cancer (sub)types coupled to spatio-temporal interactions with substrates could decide the pro- or anti-cancer role of DYRK2. The current review aims to provide a balanced and critical appreciation of the literature-to-date highlighting top substrates such as p53, c-Myc, c-Jun, HSF1, proteasome or NOTCH1, to discuss DYRK2 inhibitors available to the scientific community, and to shed light on this duality of pro- and anti-tumorigenic roles of DYRK2.
Adhesion molecules during somitogenesis in the avian embryo.
