GREB1, a novel target of Wnt signaling, promotes development of hepatoblastoma by suppressing TGFß signaling

The ß-catenin mutation is frequently observed in hepatoblastoma (HB), but the underlying mechanism by which Wnt/ß-catenin signaling induces HB tumor formation is unknown. We found that expression of growth regulation by estrogen in breast cancer 1 (GREB1) depends on Wnt/ß-catenin signaling in HB patients. GREB1 was localized to the nucleus where it bound Smad2/3 in a competitive manner with p300 and inhibited TGFß signaling, thereby promoting HepG2 HB cell proliferation. Forced expression of ß-catenin, YAP, and c-Met induced HB-like mouse liver tumor (BYM mice), with an increase in GREB1 expression and HB markers. Depletion of GREB1 strongly suppressed marker gene expression and HB-like liver tumorigenesis, and instead enhanced TGFß signaling in BYM mice. Furthermore, antisense oligonucleotides for GREB1 suppressed the formation of HepG2 cell-induced tumors and HB-like tumors in vivo. We propose that GREB1 is a novel target molecule of Wnt/ß-catenin signaling and required for HB progression. Overall design: RNA-sequencing analyses were performed in HepG2 cells transfected with control or ß-catenin siRNA in triplicates.