Reduced nucleic ZHX2 involves in oncogenic activation of glypican 3 in human hepatocellular carcinoma

Glypican 3 (GPC3) has been paid particular attention owing to its potential as diagnosis marker for hepatocellular carcinoma (HCC). Identifying the mechanisms regulating the reactivation of GPC3 in HCC appears to be clinically meaningful. Previous study identified zinc-fingers and homeoboxes 2 (ZHX2) as transcriptional factor responsible for postnatal repression of GPC3 in mice. Here, in this study, we provided the first evidence that down regulated ZHX2 is responsible for GPC3 reactivation in HCC. First, inverse correlation of ZHX2 with GPC3 expression was shown in cultured liver cell lines. Second, ZHX2 overexpression significantly decreased GPC3 expression, while ZHX2 knockdown effectively increased GPC3 level in different HCC cell lines. Consistently, dual luciferase and ChIP assay showed that ZHX2 dose-dependently suppressed GPC3 promoter activity by binding with the core promoter. More importantly, immunohistochemical staining demonstrated the inverse correlation between nuclear ZHX2 with GPC3 expression in HCC tissues. Further in vitro analysis showed that nuclear translocation was crucial for ZHX2 mediated repression on GPC3 transcription. Taken together, our results prove that ZHX2 suppresses GPC3 transcription by binding with its core promoter and reduced nucleic ZHX2 expression may be involved in GPC3 reactivation in HCC.