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

Shinji Matsumoto, Taku Yamamichi, Koei Shinzawa, Yuuya Kasahara, Satoshi Nojima, Takahiro Kodama, Satoshi Obika, Tetsuo Takehara, Eiichi Morii, Hiroomi Okuyama and Akira Kikuchi ()
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Shinji Matsumoto: Osaka University
Taku Yamamichi: Osaka University
Koei Shinzawa: Osaka University
Yuuya Kasahara: Osaka University
Satoshi Nojima: Osaka University
Takahiro Kodama: Osaka University
Satoshi Obika: Osaka University
Tetsuo Takehara: Osaka University
Eiichi Morii: Osaka University
Hiroomi Okuyama: Osaka University
Akira Kikuchi: Osaka University

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-11533-x

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