Chalcone suppresses tumor growth through NOX4-IRE1α sulfonation-RIDD-miR-23b axis

Chalcone is a polyphenolic compound found abundantly in natural plant components. They have been acclaimed as potential antitumor compounds in multiple tumor cells. However, not much attention has been paid to elucidate its antitumor mechanism of action. Here, chalcone was demonstrated to trigger endoplasmic reticulum (ER) stress-induced apoptosis through sulfonation of IRE1α by ER-localized NADPH oxidase 4 (NOX4). IRE1α-sulfonation at a cysteine residue was shown to induce "regulated IRE1α-dependent decay" (RIDD) of mRNA rather than specific splicing of XBP1. The IRE1α sulfonation-induced RIDD degraded miR-23b, enhancing the expression of NOX4. The expression of NOX4 was also upregulated in breast, and prostate cancer tissue. In chalcone-administered mice in vivo, tumor growth was regressed by the consistent mechanisms "NOX4-IRE1α sulfonation-RIDD". Similarly, NOX4 activation and IRE1α sulfonation were also highly increased under severe ER stress conditions. Together, these findings suggest chalcone as a lead anticancer compound where it acts through NOX4-IRE1α-RIDD-miR-23b axis providing a promising vision of chalcone derivatives' anticancer mechanism.