Prosurvival function of the nuclear transport factor Cellular Apoptosis Susceptibility (CAS) in hepatocarcinogenesis

Abstract

There is emerging evidence that malignant progression can involve deregulated expression and function of nuclear transport factors. As an important member of the nucleo-cytoplasmic transport machinery the karyopherin Cellular Apoptosis Susceptibility (CAS) re-shuttles importin-α from the nucleus to the cytoplasm. As indicated by its name CAS was reported to have proapoptotic functions under stressed conditions. Surprisingly, we found that under unstressed conditions CAS knockdown in hepatoma cell lines leads to an increase of apoptosis and to attenuated cell growth, proliferation, migration, and invasion. Consistent with these findings overexpression of CAS was detected on mRNA and protein level in the majority of hepatocellular carcinoma (HCC) tissue samples analyzed. To identity potential downstream targets of CAS we performed gene expression arrays indicating that CAS depletion is followed by downregulation of the X-linked inhibitor of apoptosis (XIAP). Furthermore, direct knockdown of XIAP partially phenocopied the effects observed upon CAS ablation. Finally, we found that CAS is a repression target of p53.