SCN1A regulates the cell cycle of mesenchymal stromal cells through APC/C-mediated CCNA2 degradation

Although voltage-gated sodium channels are known to be expressed in both excitable and non-excitable cells, their roles in non-excitable cells remain poorly understood. Previously, we demonstrated that SCN1A, a voltage-gated sodium channel α-subunit, is involved in the cell cycle in mesenchymal stromal cells (MSCs) through the degradation of CDK2. Here, we analyzed the role of SCN1A in regulating the degradation of CCNA2, which is essential for CDK2 activation. SCN1A knockdown reduced the CCNA2 protein level in MSCs and inhibited the transition from G1 phase to S phase of the cell cycle. Although lysosome inhibitors had no effect on CCNA2 levels, proteasome inhibitors increased CCNA2 levels in SCN1A-knockdown MSCs. Furthermore, cycloheximide chase analysis demonstrated that SCN1A knockdown accelerated proteasome-dependent degradation of CCNA2. In addition, SCN1A knockdown increased the expression of the APC/C component genes CDC26 and ANAPC13 and decreased the expression of APC/C inhibitor gene MAD2L1 and BUB1B. The MAD2L1 inhibitor M2I-1 reduced CCNA2 levels and inhibited the transition from G1 phase to S phase. These results suggested that SCN1A regulates cell cycle progression in MSCs by controlling the APC/C-associated ubiquitin-proteasome-mediated degradation of CCNA2. This study demonstrated a novel cell cycle regulatory function of SCN1A in non-excitable cells and provided new insights into the mechanisms governing MSC proliferation and the understanding of SCN1A-related diseases.