Please use this identifier to cite or link to this item: http://hdl.handle.net/10397/89438
Title: ZBTB20 regulates WNT/CTNNB1 signalling pathway by suppressing PPARG during hepatocellular carcinoma tumourigenesis
Authors: To, JC 
Chiu, AP 
Tschida, BR
Lo, LH 
Chiu, CH 
Li, XX 
Kuka, TP
Linden, MA
Amin, K
Chan, WC 
Bell, JB
Moriarity, BS
Largaespada, DA
Keng, VW 
Issue Date: Apr-2021
Source: JHEP reports, Apr. 2021, v. 3, no. 2, 100223
Abstract: 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 (Trp53) 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, which leads to activation of the WNT/CTNNB1 signalling pathway in HCC tumourigenesis.
Lay summary: ZBTB20 has been implicated as a potential oncogene in liver cancer. Herein, we uncover its important role in liver cancer development. We show that it interacts with PPARG to upregulate the WNT/CTNNB1 signalling pathway, leading to tumourigenesis.
Keywords: Hepatocellular carcinoma
Sleeping Beauty
Reverse genetic screen
ZBTB20
PPARG
CTNNB1
Publisher: Elsevier
Journal: JHEP reports 
EISSN: 2589-5559
DOI: 10.1016/j.jhepr.2020.100223
Rights: © 2020 The Author(s). Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
The following publication To, J. C., Chiu, A. P., Tschida, B. R., Lo, L. H., Chiu, C. H., Li, X. X., ... & Keng, V. W. (2021). ZBTB20 regulates WNT/CTNNB1 signalling pathway by suppressing PPARG during hepatocellular carcinoma tumourigenesis. JHEP Reports, 3(2), 100223 is available at https://doi.org/10.1016/j.jhepr.2020.100223
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