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

## TL;DR

This study shows that inhibiting a potassium channel in prostate cancer cells activates a tumor suppressor gene, reducing cancer stem cell properties.

## Contribution

The study identifies a novel transcriptional regulatory axis involving KCa1.1, Nrf2, and FBXW7 in prostate cancer spheroids.

## Key findings

- KCa1.1 inhibition activates FBXW7 transcription through the Akt-Nrf2-CEBPD-miR223 axis in LNCaP spheroids.
- FBXW7 activation reduces CSC markers like c-Myc and membrane KCa1.1 levels in prostate cancer spheroids.
- miR223 mimics and CEBPD inhibition reduce FBXW7 transcriptional activity in the spheroid model.

## Abstract

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, KCa1.1, 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 KCa1.1 inhibition-induced activation of FBXW7 reduced (1) KCa1.1 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 KCa1.1 inhibition-induced FBXW7 activation suppressed CSC conversion in KCa1.1-positive cancer cells.