Transcriptional Up-Regulation of FBXW7 by KCa1.1 K+ Channel Inhibition through the Nrf2 Signaling Pathway in Human Prostate Cancer LNCaP Cell Spheroid Model

The tumor suppressor gene F-box and WD repeat domain-containing (FBXW) 7 reduces Cancer stemness properties by promoting the protein degradation of pluripotent stem cell markers. We recently demonstrated the transcriptional repression of FBXW7 by the three-dimensional (3D) spheroid formation of several Cancer cells. In the present study, we found that the transcriptional activity of FBXW7 was promoted by the inhibition of the CA²⁺-activated K⁺ channel, K_CA1.1, in a 3D spheroid model of human prostate Cancer LNCaP cells through the Akt-Nrf2 signaling pathway. The transcriptional activity of FBXW7 was reduced by the siRNA-mediated inhibition of the CCAAT-enhancer-binding protein C/EBP δ (CEBPD) after the transfection of miR223 mimics in the LNCaP spheroid model, suggesting the transcriptional regulation of FBXW7 through the Akt-Nrf2-CEBPD-miR223 transcriptional axis in the LNCaP spheroid model. Furthermore, the K_CA1.1 inhibition-induced activation of FBXW7 reduced (1) K_CA1.1 activity and protein levels in the plasma membrane and (2) the protein level of the Cancer stem cell (CSC) markers, c-Myc, which is a molecule degraded by FBXW7, in the LNCaP spheroid model, indicating that K_CA1.1 inhibition-induced FBXW7 activation suppressed CSC conversion in K_CA1.1-positive Cancer cells.

C/EBP; Ca2+-activated K+ channel; FBXW7; KCa1.1; Nrf2; c-Myc; cancer stemness; miR223; protein degradation; spheroid.