Regulation of Snail stability by HIPK2-mediated phosphorylation (555.7)

Local invasion appears to bean initial and essential step in the malignancy of carcinoma and it leads to the generation of fatal distant metastasis. During tumor invasion, changes in cell adhesion and migration are reminiscent of an important developmental process termed epithelial-mesenchymal transition(EMT). Snail is a critical regulator of multiple signaling pathways that lead to EMT and its expression is tightly regulated. In this study, we show that HIPK2, a novel negative regulator of Snail, targets the Snail for phosphorylationleading to proteasomal degradation under normal culture condition. HIPK2 phosphorylates at multiple serine residues which partially overlaps with the GSK3β-mediated hosphorylation sites. In hypoxic condition, however, HIPK2 is destabilized in a Siah-2-dependent manner and Snail is stabilized.These results demonstrate that HIPK2 is a novel regulator of Snail at the protein level and participate in EMT through regulation of Snail stability.