Transcriptional regulation of TAX1BP2, a putative tumor suppressor in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) becomes a critical health threat in Hong Kong，due to highly metastatic nature, late diagnosis and limited choice of chemotherapy. TAX1 binding protein 2 (TAX1BP2) is first identified as a novel binding partner of TAX1, an oncoprotein encoded in HTLV I virus. It is frequently underexpressed in HCC and this underexpression is associated with poorer survival outcome of patient. I examined the transcriptional regulation of TAX1BP2 to understand how TAX1BP2 is downregulated in HCC. I predicted the potential transcriptional factors binding sites on TAX1BP2 promoter by LASAGNA software, and showed that deletion of the binding sites for HNF4α resulted in a significant decrease in TAX1BP2 promoter activity. Consistently, the promoter activity, mRNA and protein expression levels of TAX1BP2 were up-regulated with ectopic expression of HNF4α. Interestingly, ectopic expression of HBx, an oncoprotein encoded by HBV, was able to inhibit HNF4α and suppress TAX1BP2 protein expressio. Furthermore, ectopic expression of HNF4α can rescue the HBx mediated suppression of TAX1BP2 promoter activity, indicating that HNF4α and HBx works within the same signaling pathway. In conclusion, these results suggested that HNF4α is an activating transcription factor of TAX1BP2. The elucidation of the HBx-HNF4α-TAX1BP2 pathway provides novel insight into the molecular mechanism underlining chronic HBV infection associated hepatocarcinogenesis.