Zinc finger protein ZBTB20 is an independent prognostic marker and promotes tumor growth of human hepatocellular carcinoma by repressing FoxO1.

Heping Kan,Dingli Liu,Xianghong Li,Yuqi Huang,Jianjia Chen,Miaojiang Shu

doi:10.18632/oncotarget.7425

Abstract

Zinc finger and BTB domain-containing 20 (ZBTB20) is a new BTB/POZ-domain gene and a member of the POK family of transcriptional repressors. Notably, the role of ZBTB20 and its underlying mechanisms involved in hepatocarcinogenesis are poorly investigated. In this study, the expression of ZBTB20 was significantly overexpressed in hepatocellular carcinoma (HCC) tissues. The positive expression of ZBTB20 was associated with large tumor size, high Edmondson-Steiner grading and advanced tumor-node-metastasis (TNM) tumor stage. Additionally, HCC patients with positive expression of ZBTB20 had a poorer 5-year survival. Multivariate analyses revealed that ZBTB20 overexpression was an independent prognostic factor for HCC. Gain- and loss-of-function experiments demonstrated that ZBTB20 promoted HCC cell viability, proliferation, tumorigenicity, and cell cycle progression. Mechanistically, Cyclin D1 and Cyclin E were increased, while p21 and p27 were decreased by ZBTB20 in HCC cells. FoxO1 was inversely correlated with ZBTB20 protein expression in the same cohort of HCC specimens. We further revealed that FoxO1 was transcriptionally repressed by ZBTB20 in HCC. Moreover, restoration of FoxO1 expression partially abrogated ZBTB20-induced HCC cell proliferation and growth entry in vitro and in vivo. Collectively, these results indicate that ZBTB20 may serve as a prognostic marker and promotes tumor growth of HCC via transcriptionally repressing FoxO1.

Highlights

Hepatocellular carcinoma (HCC) is the fifth most common malignancy and the third cause of cancer-related death worldwide [1]
We found that the levels of Zinc finger and BTB domain-containing 20 (ZBTB20) mRNA and protein in HCC tissues were significantly higher than those in matched normal tumor-adjacent tissues (P < 0.01, Figure 1A and 1B)
Hepatocellular carcinoma (HCC) is a complex disease caused by a combination of both genetic and environmental factors [29]

Summary

Introduction

Hepatocellular carcinoma (HCC) is the fifth most common malignancy and the third cause of cancer-related death worldwide [1]. The molecular mechanisms involved in the initiation and progression of HCC remain poorly understood. ZBTB20 participate in various cellular functions including transcriptional regulation, cellular proliferation, tumorigenesis, ion channel assembly, and chromatin remodeling [8,9,10]. A subset BTB/POZ protein has been implicated in human cancer, such as BCL-6, PLZF, and NAC-1. ZBTB20 regulates β cell function and glucose homeostasis in mice model [16]. Increasing studies have disclosed the aberrant expression and role of ZBTB20 in carcinogenesis. Wang et al reported that increased expression of ZBTB20 was associated with poor prognosis in HCC patients [18]. Weng et al demonstrated that ZBTB20 was down-regulated following 70% hepatectomy in mice, suggesting that ZBTB20 may inhibit cell proliferation in the hepatocytes [19]. The role of ZBTB20 in HCC progression remains uncharacterized

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Conclusion