摘要
Tbx3,a transcriptional repressor,is essential in the organogenesis of vertebrates,stem cell self-renewal and differentiation,and the carcinogenesis of multiple tumor types.However,the mechanism by which Tbx3 participates in the metastasis of hepatocellular carcinoma(HCC)remains largely unknown.In this study,we show that Tbx3 was dramatically upregulated in clinical HCC samples and that elevated expression of Tbx3 promoted cancer progression.To determine the underlying mechanism,systematic glycine scan mutagenesis and deletion assays were performed.We identified two critical motifs,^(585)LFSYPYT^(591)and^(604)HRH^(606),that contribute to the repression of transcriptional activity.These motifs are also essential for Tbx3 to promote cell migration and metastasis both in vitro and in vivo via the suppression of E-cadherin expression.More importantly,Tbx3 directly interacts with HDAC5 via these motifs,and an HDAC inhibitor blocks Tbx3-mediated cell migration and the downregulation of E-cadherin in HCC.As Tbx3 is involved in the carcinogenesis of multiple types of human cancers,our findings suggest an important target for anticancer drug development.
基金
This study was supported by grants from The Science Technology and Innovation Committee of Shenzhen Municipality(JSGG20151030110921727,JCYJ20170818100531426,JCYJ20170306091121656)
the Planned Science and Technology Project of Guangdong Province(2017A020215004)
NSFC(No.81471964,81671995,81702510)
The Start-up Fund and Match Fund from The City University of Hong Kong(9680149,9610330).
