AKIP1 promotes early recurrence of hepatocellular carcinoma through activating the Wnt/ß-catenin/CBP signaling pathway.

ABSTRACT

The early recurrence of hepatocellular carcinoma (HCC) is the main obstacle for long-term survival of patients. Wnt/ß-catenin signaling has been involved in the development and progression of HCC. However, the molecular changes that link Wnt/ß-catenin activation and HCC early recurrence remain poorly understood. Here we identified AKIP1 as a binding partner of ß-catenin. AKIP1 interacted with and sustained ß-catenin in the nuclear by blocking its interaction with adenomatous polyposis coli protein (APC). Moreover, AKIP1 enhanced the protein kinase A catalytic subunit (PKAc)-mediated phosphorylation of ß-catenin, leading to recruitment of cyclic AMP response element-binding protein (CBP) and activation of ß-catenin downstream transcription. Increased AKIP1 expression was observed in HCC clinical samples and correlated with early recurrence and poor prognosis of HCC. AKIP1 promoted invasion and colony outgrowth in vitro and increased intrahepatic and lung metastasis in vivo. Treatment with a CBP inhibitor ICG-001 effectively inhibited the metastatic progression of HCC tumors that had elevated AKIP1 in both cell line and patient-derived xenograft mouse models. Our findings not only establish AKIP1 as a novel regulator of Wnt/ß-catenin signaling as well as HCC early recurrence but also highlight targeting the AKIP1/ß-catenin/CBP axis as attractive therapies for combating HCC metastatic relapse.