The 14-3-3σ/GSK3β/β-catenin/ZEB1 regulatory loop modulates chemo-sensitivity in human tongue cancer

Here we demonstrated that chemotherapy induced 14-3-3 sigma expression in tongue cancer (TC) cells and overexpressed 14-3-3 sigma sensitized TC cells to chemotherapy especially in multidrug resistant TC (MDR-TC) cells. In agreement, 14-3-3 sigma knockdown enhanced resistance of TC cells to chemotherapy. Mechanically, we found 14-3-3 sigma physically bound to GSK3 beta in protein level and the binding inhibited beta-catenin signaling. Coincidentally, chemotherapy as well as 14-3-3 sigma overexpression led to increase of GSK3 beta protein level. Increased GSK3 beta protein sensitized TC cells to chemotherapy. Moreover, deregulation of 14-3-3 sigma/ GSK3 beta/beta-catenin axis led to overexpressed ZEB1 in TC cells, especially in MDR-TC cells. As a negative feedback loop, ZEB1 bond to 14-3-3 sigma promoter to enhance promoter hypermethylation in TC cells. Promoter hypermethylation resulted into the decrease of 14-3-3 sigma expression. Importantly, a positive correlation was observed between 14-3-3 sigma and GSK3 beta protein expression in TC tissues from patients receiving chemotherapy. High levels of 14-3-3 sigma and GSK3 beta were associated with better prognosis in TC patients.