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

Abstract

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.