Ubiquitin-like protein FAT10 promotes the invasion and metastasis of hepatocellular carcinoma by modifying β-catenin degradation.

Abstract

The ubiquitin-like protein FAT10 and the homeobox protein HOXB9 each promote metastatic progression in hepatocellular carcinoma (HCC). In this study, we investigated the clinicopathologic significance of FAT10 and HOXB9 in HCC and investigated a mechanistic role for FAT10 in HOXB9-mediated invasiveness and metastasis. Relative to adjacent normal tissues, FAT10 and HOXB9 were markedly overexpressed in HCC, where a positive correlation in their expression and associated malignant characteristics were found. RNAi-mediated silencing of FAT10 decreased HOXB9 expression and inhibited HCC invasion and metastasis in vitro and in vivo. The effects of FAT10 silencing were reversed by HOXB9 overexpression, whereas RNAi-mediated silencing of HOXB9 decreased HCC invasion and metastasis driven by FAT10 overexpression. Mechanistically, FAT10 regulated HOXB9 expression by modulating the β-catenin/TCF4 pathway, directly binding to β-catenin and preventing its ubiquitination and degradation. Together, our results identified a novel HCC regulatory circuit involving FAT10, β-catenin/TCF4, and HOXB9, the dysfunction of which drives invasive and metastatic character in HCC. Cancer Res; 74(18); 5287-300. ©2014 AACR.

• Authors: Rongfa Yuan, Kai Wang, Junwen Hu, Chen Yan, Ming Li, Xin Yu, Xiuxia Liu, Jun Lei, Wuhua Guo, Linquan Wu, Kui Hong, Jianghua Shao
• Journal: Cancer research (Cancer Res) Vol. 74 Issue 18 Pg. 5287-300 (Sep 15 2014) ISSN: 1538-7445 [Electronic] United States
• PMID: 25056121 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
• HOXB9 protein, human
• Homeodomain Proteins
• TCF4 protein, human
• Transcription Factor 4
• Transcription Factors
• UBD protein, human
• Ubiquitins
• beta Catenin

Topics

• Animals
• Basic Helix-Loop-Helix Leucine Zipper Transcription Factors (genetics, metabolism)
• Carcinoma, Hepatocellular (genetics, metabolism, pathology)
• Cell Line, Tumor
• Female
• Heterografts
• Homeodomain Proteins (genetics, metabolism)
• Humans
• Liver Neoplasms (genetics, metabolism, pathology)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Middle Aged
• Neoplasm Invasiveness
• Neoplasm Metastasis
• Transcription Factor 4
• Transcription Factors (genetics, metabolism)
• Transfection
• Ubiquitins (genetics, metabolism)
• beta Catenin (metabolism)