GREB1, a novel therapeutic target of Wnt signaling, promotes the development of hepatoblastoma by suppressing TGFβ signaling

Yamamichi Taku, Matsumoto Shinji, Okuyama Hiroomi, Kikuchi Akira

doi:10.11412/jspho.57.116

Hepatoblastoma (HB), the most common pediatric liver cancer, has the highest association with the mutational activation of β-catenin. However, the underlying mechanism by which Wnt/β-catenin signaling induces HB tumor formation is unknown. Here, we identify growth regulation by estrogen in breast cancer 1 (GREB1) as a previously unknown target gene of Wnt/β-catenin signaling. GREB1 promoted the proliferation and suppressed the differentiation of HB cells. GREB1 bound Smad2/3 and competed with histone acetyl transferase p300 in the nucleus, resulting in the inhibition of TGFβ-dependent cytostasis. GREB1 was overexpressed in tumor lesions of 10/11 HB cases (90.9%) and in a public dataset of patients with HB. The region-specific expression pattern of GREB1 in HB tissues tended to be positively correlated with the accumulation of β-catenin. Forced expressions of β-catenin, YAP, and c-Met (BYM) induced HB-like liver tumor in mice, with increases in the expression levels of GREB1 and HB marker genes; GREB1 knockdown suppressed the expression of HB marker genes and tumor formation in BYM mice. Furthermore, we synthesized amido-bridged nucleic acid (AmNA)-modified antisense oligonucleotides (ASOs) that target human GREB1. GREB1 depletion by ASO injection suppressed HepG2-derived liver tumor formation in mice. These findings uncover a previously unrecognized involvement of the Wnt/β-catenin-GREB1-Smads axis in HB pathogenesis, suggesting that GREB1 represents a potential therapeutic target for β-catenin-driven HB.

<i>GREB1</i>, a novel therapeutic target of <i>Wnt</i> signaling, promotes the development of hepatoblastoma by suppressing <i>TGFβ</i> signaling

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