GREB1 induced by Wnt signaling promotes development of hepatoblastoma by suppressing TGF\u03b2 signaling

Shinji Matsumoto,Takahiro Kodama,Koei Shinzawa,Akira Kikuchi,Eiichi Morii,Satoshi Obika,Tetsuo Takehara,Taku Yamamichi,Satoshi Nojima,Yuuya Kasahara,Hiroomi Okuyama

doi:10.1038/s41467-019-11533-x

Abstract

The β-catenin mutation is frequently observed in hepatoblastoma (HB), but the underlying mechanism by which Wnt/β-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/β-catenin signaling in HB patients. GREB1 is localized to the nucleus where it binds Smad2/3 in a competitive manner with p300 and inhibits TGFβ signaling, thereby promoting HepG2 HB cell proliferation. Forced expression of β-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 TGFβ 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/β-catenin signaling and required for HB progression.

Highlights

The β-catenin mutation is frequently observed in hepatoblastoma (HB), but the underlying mechanism by which Wnt/β-catenin signaling induces HB tumor formation is unknown
We identified GREB1 as an uncharacterized target gene expressed by Wnt/β-catenin signaling, and found that GREB1 expression is critical for HB cell proliferation
This study clarified the molecular mechanisms by which GREB1 promotes HB cell proliferation

Summary

Introduction

The β-catenin mutation is frequently observed in hepatoblastoma (HB), but the underlying mechanism by which Wnt/β-catenin signaling induces HB tumor formation is unknown. We show that expression of growth regulation by estrogen in breast cancer 1 (GREB1) depends on Wnt/β-catenin signaling in HB patients. Depletion of GREB1 strongly suppresses marker gene expression and HB-like liver tumorigenesis, and instead enhances TGFβ signaling in BYM mice. GREB1 could be a potential therapeutic target for hormonesensitive cancers It remains unclear whether GREB1 expression is involved in tumor formation in cancers that are not hormone-sensitive. We identified GREB1 as an uncharacterized target gene expressed by Wnt/β-catenin signaling, and found that GREB1 expression is critical for HB cell proliferation. GREB1 was frequently detected together with β-catenin in the tumor lesions of HB patients, and GREB1 inhibited TGFβ signaling, and thereby promoting HB cell proliferation. We propose a function of GREB1 in HB cells and the possibility of a therapeutic strategy for HB using amido-bridged nucleic acid (AmNA)-modified antisense oligonucleotides (ASOs) that target GREB1

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