Silencing of voltage-gated potassium channel K(V)9.3 inhibits proliferation in human colon and lung carcinoma cells

Voltage-gated potassium (K(v)) channels are known to be involved in cancer development and cancer cell proliferation. K(V)9.3, an electronically silent subunit, forms heterotetramers with K(V)2.1 in excitable cells and modulates its electrophysiological properties. However, the role of K(V)9.3 alone in non-excitable cancer cells has not been studied. Here, we evaluated the effect of silencing K(V)9.3 on cancer cell proliferation in HCT15 colon carcinoma cells and A549 lung adenocarcinoma cells. We confirmed the expression of K(V)9.3 mRNA in HCT15 and A549 cells and showed that silencing K(V)9.3 using small interfering RNA caused G0/G1 cell cycle arrest and alterations in cell cycle regulatory proteins in both HCT15 and A549 cells without affecting apoptosis. Also, stable knockdown of K(V)9.3 expression using short-hairpin RNA inhibited tumor growth in SCID mouse xenograft model. Using a bioinformatics approach, we identified Sp1 binding sites in the promoter region of the gene encoding K(V)9.3. We further found that Sp1 bound to this region and showed that the Sp1 inhibitor, mithramycin A, induced a concentration-dependent decrease in K(V)9.3 expression. Taken together, these data suggest that knockdown of K(V)9.3 inhibits proliferation in colon carcinoma and lung adenocarcinoma cell lines and may be regulated by Sp1.