Emerging roles of DYRK2 in cancer

Abstract

Over the last decade, the CMGC kinase DYRK2 has been reported as a tumor suppressor across various cancers triggering major antitumor and proapoptotic signals in breast, colon, liver, ovary, brain, and lung cancers, with lower DYRK2 expression correlated with poorer prognosis in patients. Contrary to this, various medicinal chemistry studies reported robust antiproliferative properties of DYRK2 inhibitors, whereas unbiased ‘omics’ and genome-wide association study-based studies identified DYRK2 as a highly overexpressed kinase in various patient tumor samples. A major paradigm shift occurred in the last 4 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 misfolded/tumor-suppressor proteins while also promoting the nuclear stability and transcriptional activity of its substrate, heat-shock factor 1 triggering protein folding. Together, DYRK2 regulates proteostasis and promotes protumorigenic survival for specific cancers. Indeed, potent and selective small-molecule inhibitors of DYRK2 exhibit in vitro and in vivo anti-tumor activity in triple-negative breast cancer and myeloma models. However, with conflicting and contradictory reports across different cancers, the overarching role of DYRK2 remains enigmatic. Specific cancer (sub)types coupled to spatiotemporal interactions with substrates could decide the procancer or anticancer 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, heat-shock factor 1, proteasome, or NOTCH1, to discuss DYRK2 inhibitors available to the scientific community and to shed light on this duality of protumorigenic and antitumorigenic roles of DYRK2.

Pan-cancer organoid validation of tumor outlier chromosomal amplification events

“…Here, DYRK2 strongly promoted in vitro proliferation and in vivo 12 tumorigenicity of oral mucosal organoids, as a highly relevant model for head and neck squamous cell carcinoma. DYRK2 is a family member of relatively understudied tyrosine kinases that phosphorylate histones and other substrates (Tandon et al, 2021). Our studies suggest the potential dependency of DYRK2-amplifications in oral cancers and corresponding efficacy of DYRK2 selective inhibitors.…”

“…DYRK2 amplification is seen in approximately 5% of HNSCC (Cancer Genome Atlas, 2015). DYRK2 is thought to be required for tumor growth via proteasome phosphorylation (Guo et al, 2016) and induces p53dependent apoptosis to DNA damage (Taira et al, 2007;Tandon et al, 2021). Of the DYRK2 ORFs screened, we found greater enrichment of ORFs mapping to the isoform 2 transcript variant.…”

Characterising sex differences of autosomal DNA methylation in whole blood using the Illumina EPIC array

“…Interestingly, as well as DYRK2 and GABPA being the genes annotated to the most significant saDMPs hypermethylated in females and males respectively, they were also the two most significant saDMRs, suggesting these regions could account for important sex biases observed in some diseases. This is further supported by the fact that GABPA has also been heavily associated with early onset of Alzheimers disease, Parkinsons disease, breast cancer and autism (68) and DYRK2 implication in cancer (69). Our KEGG term analysis at those saDMPs hypermethylated in females also implicated many cancer related KEGG terms including thyroid cancer, endometrial cancer, non-small cell lung cancer and more (Figure 2B).…”

Targeting dual-specificity tyrosine phosphorylation-regulated kinase 2 with a highly selective inhibitor for the treatment of prostate cancer

“…Class I and class II DYRKs are mainly localized in the nucleus and cytoplasm, respectively. Among class II DYRKs, DYRK2 is most deeply studied, which plays important while controversial roles in human cancers 18 , 19 . Previously, DYRK2 was primarily considered as a cancer suppressor, which can promote phosphorylation of P53 to induce apoptosis 20 , 21 , facilitate degradation of c-JUN and c-MYC to inhibit the transition of the cell cycle from G1 to S phase 22 , 23 , and accelerate the degradation of snail to suppress epithelial-to-mesenchymal transition (EMT) and cell migration and so on 24 , 25 .…”