The TET2/E-cadherin/β-catenin regulatory loop confers growth and invasion in hepatocellular carcinoma cells.

The poor outcome of hepatocellular carcinoma (HCC) is mainly due to the development of fast growth, invasion and metastasis. The role of TET2 has been implicated in some cancer types, but its role and mechanisms in HCC remains elusive. In this study, our findings indicated that TET2 expression frequently increased in HCC and that TET2 expressional upregulation correlated with HCC progression. TET2 knockdown inhibited HCC cells proliferation in vitro and growth in vivo, and inhibited the invasion potential of HCC cells. Mechanically, TET2 knockdown upregulated E-cadherin expression and then attenuated β-catenin transactivation in HCC cells. TET2 repressed E-cadherin expression via recruited HDAC1 to E-cadherin promoter to reduce the H3K9Ac and H4K16Ac levels. Moreover, β-catenin signaling transcriptionally regulated TET2 expression to form a positive feedback in HCC cells. These findings indicate that the dysregulation of TET2/E-cadherin/β-catenin regulatory loop is a critical oncogenic event in HCC progression.