DYRK1A suppression attenuates HIF-1α accumulation and enhances the anti-liver cancer effects of regorafenib and sorafenib under hypoxic conditions

Hypoxia promotes drug resistance and induces the expression of hypoxia inducible factor (HIF)-1α in liver cancer cells. However, to date, no selective HIF-1α inhibitor has been clinically approved. The aim of this study is to investigate a drug-targetable molecule that can regulate HIF-1α under hypoxia. The present study demonstrated that hyperactivation of dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A)/HIF-1α signaling was associated with an increased risk of liver cancer. In addition, DYRK1A knockdown using small interfering RNA transfection or treatment with harmine, a natural alkaloid, significantly reduced the protein expression levels of HIF-1α in liver cancer cells under hypoxic conditions in vitro. Conversely, DYRK1A overexpression-vector transfection in liver cancer cell lines notably induced HIF-1α expression under the same conditions. Furthermore, DYRK1A was shown to interact and activate STAT3 under hypoxia to regulate HIF-1α expression. These findings indicated that DYRK1A may be a potential upstream activator of HIF-1α and positively regulate HIF-1α via the STAT3 signaling pathway in liver cancer cells. Additionally, treatment with harmine attenuated the proliferative ability of liver cancer cells under hypoxic conditions using sulforhodamine B and colony formation assay. Furthermore, DYRK1A knockdown could significantly enhance the anti-liver cancer effects of regorafenib and sorafenib under hypoxia. Co-treatment with harmine and either regorafenib or sorafenib also promoted cell death via the STAT3/HIF-1α/AKT signaling pathway under hypoxia using PI staining and western blotting. Overall, the results from the present study suggested that DYRK1A/HIF-1α signaling may be considered a novel pathway involved in chemoresistance, thus providing a potentially effective therapeutic regimen for treating liver cancer.