The potassium channel KCa3.1 promotes cell proliferation by activating SKP2 and metastasis through the EMT pathway in hepatocellular carcinoma

The intermediate conductance calcium‐activated potassium channel (KCa3.1) plays an important role in maintaining intracellular calcium homeostasis and is involved in the tumorigenesis of many human cancers. However, it is unknown whether KCa3.1 plays a role in the genesis of hepatocellular carcinoma (HCC), one of the most common malignant tumors worldwide with a very poor prognosis. In our study, we found that the expression of KCa3.1 was significantly elevated in poorly differentiated HCC tissues compared to adjacent noncancerous tissues. In vitro and in vivo experiments showed that KCa3.1 could promote cell proliferation, migration, and invasion of HCC. Mechanistically, KCa3.1 promoted cell cycle progression and migration and invasion of HCC cells by activating S‐phase protein kinase 2 (SKP2) to trigger the degradation of p21 and p27 and targeting Reelin (RELN) to induce epithelial‐mesenchymal transition (EMT), respectively. Taken together, our results demonstrate that KCa3.1 plays an important role in the genesis and progression of HCC, implying that it might be a promising therapeutic target in HCC. What's new? The calcium‐activated potassium channel KCa3.1, which regulates cell volume and intracellular calcium homeostasis, is thought to influence the development of various cancers, including hepatocellular carcinoma (HCC). Here, the expression of KCa3.1 was found to be significantly elevated in poorly differentiated HCC tissues compared with adjacent noncancerous tissues. In HCC cell lines, expression of KCa3.1 promoted cell cycle progression via activation of the cell cycle regulator SKP2, with subsequent p21 and p27 degradation. KCa3.1 expression further promoted migration and invasion via RELN targeting to induce epithelial‐mesenchymal transition. KCa3.1 may be a promising target for the development of novel HCC therapies.