Valproic Acid inhibits proliferation and promotes apoptosis of peripheral T cell lymphoma cells via the miRNA-3196/KCNK3 signaling axis

Objective The aim of this study was to clarify the treatment effect and potential mechanism of Alproic acid (VPA) on peripheral T cell lymphomas (PTCLs). Methods CCK-8 and EdU were used to detect cell proliferation. The mRNA expression of miR-3196 and KCNK3 was detected by qRT-PCR. Biochemical experiments were used to detect changes in the content of ATP, lactate level, and glucose content. Flow cytometry was applied to determine the apoptotic rate and ROS levels. Western blot was used to detect the protein expression of apoptotic proteins, PI3K/AKT pathway and KCNK3. GEO database and miRTarBase and starbase2.0 software were used to identify the target genes of miR-3196. Results VPA greatly inhibited PTCLs cells proliferation and promoted the expression of miR-3196 in a dose-dependent manner. Compared with the control group, VPA and miR-3196 mimics significantly increased the apoptosis rate, Bax and cleaved-caspase-3 expression, lactate level, ROS expression, and glucose content ( P  < 0.01), and significantly decreased the cell proliferation, ATP production, and the expression of Bcl-2, p-PI3K and p-AKT ( P  < 0.01) in the PTCLs cells. However, the miR-3196 inhibitor had the opposite effect to VPA and mimics. Moreover, the combination of VPA and miR-3196 mimics has the most obvious effect. Moreover, KCNK3 was found to be a potential target gene of miR-3196. VPA and miR-3196 mimics significantly inhibited the expression of KCNK3( P  < 0.01), and miR-3196 inhibitor the expression of KCNK3( P  < 0.01). Furthermore, si-KCNK3 promoted apoptosis and inhibited proliferation and activation of PI3K/Akt signaling pathways of PTCLs cells( P  < 0.01). VPA could significantly enhance the effect of si-KCNK3 in PTCLs cells( P  < 0.01). Conclusion VPA could inhibit the expression of KCNK3 by promoting the expression of miR-3196, and then inhibit the activation of PI3K/Akt pathway, ultimately promoting apoptosis and inhibiting proliferation of PTCLs cells.