ZBTB20 regulates WNT/CTNNB1 signalling pathway by suppressing PPARG during hepatocellular carcinoma tumourigenesis

作者：Jeffrey To, Amy P. Chiu, Barbara R. Tschida, Lilian H. Lo, Cynthia H. Chiu, Xiao-Xiao Li, Timothy P. Kuka, Michael A. Linden, Khalid Amin, Wing-Cheung Chan, Jason Bell, Branden S. Moriarity, David A. Largaespada, Vincent W. Keng · 发表于：JHEP Reports · 年份：2020 · DOI：10.1016/j.jhepr.2020.100223 · 被引用次数：50 · 研究领域：Peroxisome Proliferator-Activated Receptors、Wnt/β-catenin signaling in development and cancer、Aldose Reductase and Taurine

Background & Aims Zinc finger and BTB domain containing 20 ( ZBTB20 ) has been implicated as a potential oncogene in liver cancer. However, knockout studies have shown it to be a transcriptional repressor of the alpha-foetoprotein ( Afp ) gene in adult liver, and reduced levels of ZBTB20 allow for upregulation of AFP with increased tumour severity in certain cases of hepatocellular carcinoma (HCC). As there are many discrepancies in the literature regarding its role in liver tumourigenesis, the aim of this study was to elucidate the role of ZBTB20 in HCC tumourigenesis. Methods A reverse genetic study using the Sleeping Beauty ( SB ) transposon system in mice was performed to elucidate the role of ZBTB20 in HCC tumourigenesis. In vitro ZBTB20 gain- and loss-of-function experiments were used to assess the relationship amongst ZBTB20, peroxisome proliferator activated receptor gamma (PPARG) and catenin beta 1 (CTNNB1). Results Transgenic overexpression of ZBTB20 in hepatocytes and in the context of transformation related protein ( T r p53 ) inactivation induced hepatic hypertrophy, activation of WNT/CTNNB1 signalling, and development of liver tumours. In vitro overexpression and knockout experiments using CRISPR/Cas9 demonstrated the important role for ZBTB20 in downregulating PPARG, resulting in activation of the WNT/CTNNB1 signalling pathway and its downstream effectors in HCC tumourigenesis. Conclusions These findings demonstrate a novel interaction between ZBTB20 and PPARG,...