Protein kinase CK2 activation is required for transforming growth factor β-induced epithelial-mesenchymal transition

Transforming growth factor beta (TGF beta) is overexpressed in advanced cancers and promotes tumorigenesis by inducing epithelial-mesenchymal transition (EMT), which enhances invasiveness and metastasis. Although we previously reported that EMT could be induced by increasing CK2 activity alone, it is not known whether CK2 also plays an essential role in TGF-induced EMT. Therefore, in the present study, we investigated whether TGF signaling could activate CK2 and, if so, whether such activation is required for TGF-induced EMT. We found that CK2 is activated by TGF beta treatment, and that activity peaks at 48h after treatment. CK2 activation is dependent on TGF receptor (TGFBR) I kinase activity, but independent of SMAD4. Inhibition of CK2 activation through the use of either a CK2 inhibitor or shRNA against CSNK2A1 inhibited TGF beta-induced EMT. TGF beta signaling decreased CK2 beta but did not affect CK2 alpha protein levels, resulting in a quantitative imbalance between the catalytic alpha and regulatory beta subunits, thereby increasing CK2 activity. The decrease in CK2 beta expression was dependent on TGFBRI kinase activity and the ubiquitin-proteasome pathway. The E3 ubiquitin ligases responsible for TGF beta-induced CK2 beta degradation were found to be CHIP and WWP1. Okadaic acid (OA) pretreatment protected CK2 from TGF beta-induced degradation, suggesting that dephosphorylation of CK2 beta by an OA-sensitive phosphatase might be required for CK2 activation in TGF beta-induced EMT. Collectively, our results suggest CK2 as a therapeutic target for the prevention of EMT and metastasis of cancers.