JCAD Promotes Progression of Non-alcoholic Steatohepatitis to Liver Cancer by Inhibiting LATS2 Kinase Activity

Non-alcoholic steatohepatitis-associated hepatocellular carcinoma (NASH-HCC) is a malignancy whose incidents is rapidly increasing. However, the mechanisms that drive development of HCC in a steatotic microenvironment remain unknown. Here we report that the obesity-associated protein JCAD is expressed at significantly higher levels in human NASH-HCC specimens compared to peri-carcinoma specimens. High JCAD expression was verified in multiple hepatoma cell lines. Forced overexpression of JCAD in hepatoma cells promoted tumor growth and proliferation; whereas JCAD silencing yielded opposite effects. JCAD interacted with the kinase domain of the tumor suppressor kinase LATS2, a core component of the Hippo signaling pathway. JCAD overexpression inhibited the ability of LATS2 to phosphorylate YAP in this pathway, in turn upregulating CCND1 and GLI2 to promote hepatoma cell proliferation. JCAD was induced by fatty acid overload in hepatic cells and was highly expressed in a mouse model of NASH-precarcinoma lesions, where the ratio of phospho-YAP to YAP was decreased. In human NASH-HCC specimens, JCAD expression and YAP phosphorylation patterns paralleled with the mouse model. Our findings illuminate a new role for JCAD and its critical interplay in the Hippo signaling cascade during the transition of NASH to HCC, with potential implications for therapeutic development in this setting.

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