GREB1 induced by Wnt signaling promotes development of hepatoblastoma by suppressing TGFβ signaling

The beta-catenin mutation is frequently observed in hepatoblastoma (HB), but the underlying mechanism by which Wnt/beta-catenin signaling induces HB tumor formation is unknown. Here we show that expression of growth regulation by estrogen in breast cancer 1 (GREB1) depends on Wnt/beta-catenin signaling in HB patients. GREB1 is localized to the nucleus where it binds Smad2/3 in a competitive manner with p300 and inhibits TGF beta signaling, thereby promoting HepG2 HB cell proliferation. Forced expression of beta-catenin, YAP, and c-Met induces HB-like mouse liver tumor (BYM mice), with an increase in GREB1 expression and HB markers. Depletion of GREB1 strongly suppresses marker gene expression and HB-like liver tumorigenesis, and instead enhances TGF beta signaling in BYM mice. Furthermore, antisense oligonucleotides for GREB1 suppress the formation of HepG2 cell-induced tumors and HB-like tumors in vivo. We propose that GREB1 is a target molecule of Wnt/beta-catenin signaling and required for HB progression.