CBX8 Exhibits Oncogenic Activity via AKT/{beta}-Catenin Activation in Hepatocellular Carcinoma

Deregulation of polycomb proteins influences the development and progression of hepatocellular carcinoma. Here we show that chromobox 8 (CBX8) expression is increased in hepatocellular carcinoma and correlates with poor outcome in two independent cohorts containing a total of 879 cases. Ectopic expression of CBX8 facilitated tumor growth and metastasis, whereas CBX8 silencing suppressed these effects. CBX8 efficiently activated AKT/β-catenin signaling via upregulation of the transcription factor EGR1 and miR-365-3p in a noncanonical manner: CBX8 directly bound the EGR1 promoter to enhance its activity. In the nucleus, CBX8 also interacted with EGR1 to prevent its degradation. Furthermore, CBX8 increased the transcription of miR-365a-3p, which promoted the nuclear localization of β-catenin by targeting the 3′-UTR ZNRF1. Inhibiting either EGR1 or miR-365a-3p partially rescued CBX8-mediated malignant phenotypes. In clinical samples, CBX8 expression closely correlated with EGR1, miR-365a-3p, and nuclear β-catenin. Collectively, our results show that CBX8 functions as an oncogene to upregulate EGR1 and miR-365-3p to stimulate the AKT/β-catenin pathway. This newly identified signaling axis may suggest new therapeutic strategies against hepatocellular carcinoma.Significance: Elucidation of a key new element of the β-catenin signaling pathway in liver cancer may suggest new therapeutic targets. Cancer Res; 78(1); 51–63. ©2017 AACR.

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