TAZ/Wnt-β-catenin/c-MYC axis regulates cystogenesis in polycystic kidney disease

Significance Autosomal-dominant polycystic kidney disease (ADPKD) is the most common genetic renal disease, primarily caused by germline mutation of PKD1 or PKD2, leading to end-stage renal disease. There are few cures for ADPKD, although many researchers are trying to find a cure. The Hippo signaling pathway regulates organ growth and cell proliferation. Transcriptional coactivator with PDZ-binding motif (TAZ) is a Hippo signaling effector. In this study, we demonstrated that the PKD1–TAZ–Wnt–β-catenin–c-MYC signaling axis plays a critical role in cystogenesis. Endo IWR1 treatment, which inhibited β-catenin activity via AXIN stabilization, reduced cyst growth in an ADPKD model. Our findings provide a potential therapeutic target against ADPKD and would be important for clinical translation. Autosomal-dominant polycystic kidney disease (ADPKD) is the most common genetic renal disease, primarily caused by germline mutation of PKD1 or PKD2, leading to end-stage renal disease. The Hippo signaling pathway regulates organ growth and cell proliferation. Herein, we demonstrate the regulatory mechanism of cystogenesis in ADPKD by transcriptional coactivator with PDZ-binding motif (TAZ), a Hippo signaling effector. TAZ was highly expressed around the renal cyst-lining epithelial cells of Pkd1-deficient mice. Loss of Taz in Pkd1-deficient mice reduced cyst formation. In wild type, TAZ interacted with PKD1, which inactivated β-catenin. In contrast, in PKD1-deficient cells, TAZ interacted with AXIN1, thus increasing β-catenin activity. Interaction of TAZ with AXIN1 in PKD1-deficient cells resulted in nuclear accumulation of TAZ together with β-catenin, which up-regulated c-MYC expression. Our findings suggest that the PKD1–TAZ–Wnt–β-catenin–c-MYC signaling axis plays a critical role in cystogenesis and might be a potential therapeutic target against ADPKD.