Int J Biol Sci 2019; 15(5):953-961. doi:10.7150/ijbs.30857

Research Paper

KLF4-Mediated CDH3 Upregulation Suppresses Human Hepatoma Cell Growth and Migration via GSK-3β Signaling

Li Li1, Shijun Yu1, Qiong Wu1, Ning Dou1, Yandong Li1,2✉, Yong Gao1✉

1. Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China;
2. Research Center for Translational Medicine, Shanghai East Hospital, Shanghai 200120, China

Abstract

P-cadherin (CDH3), a classical cell adhesion molecule involved in tissue integrity and cell localization, has been implicated in many types of cancer. However, little is known about its function and regulatory mechanism in hepatocellular carcinoma (HCC). Here we report that CDH3 was positively regulated by kr¨uppel-like transcription factor 4 (KLF4), which is a crucial tumor suppressor gene in HCC, at mRNA level in HCC cell lines. Luciferase reporter assay and chromatin immunoprecipitation assay indicated that KLF4 directly bound to CDH3 promoter and transcriptionally activated CDH3 expression. Consistently, CDH3 expression was closely related with KLF4 expression in patients' samples and both proteins exhibited a downregulated expression pattern in cancer samples. Functionally, enforced CDH3 expression suppressed and silenced CDH3 expression promoted HCC cell growth and migration in vitro. Mechanistically, we observed that GSK-3β was regulated by CDH3 and may function as a possible downstream effector of CDH3. Knockdown of GSK-3β showed a similar phenotype with CDH3 silencing. Taken together, these findings establish the KLF4/CDH3/GSK-3β axis as an important regulatory mechanism in HCC development.

Keywords: KLF4, CDH3, hepatocellular carcinoma, GSK-3β

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How to cite this article:
Li L, Yu S, Wu Q, Dou N, Li Y, Gao Y. KLF4-Mediated CDH3 Upregulation Suppresses Human Hepatoma Cell Growth and Migration via GSK-3β Signaling. Int J Biol Sci 2019; 15(5):953-961. doi:10.7150/ijbs.30857. Available from http://www.ijbs.com/v15p0953.htm