Functional validation of cell division cycle associated 8 (CDCA8) as a novel therapeutic target in human hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is the third most lethal cancer worldwide and remains a major challenge due to poor prognosis and limited treatment options. Cell Division Cycle Associated 8 (CDCA8) is known as a component of a chromosomal passenger complex required for stability of the bipolar mitotic spindle and it is commonly overexpressed in human HCC. However, the role of CDCA8 in HCC remains indefinable. In this study, we tested the hypothesis that specific targeting of CDCA8 is sufficient to inhibit HCC progression. Small interfering RNA (siRNA)-mediated silencing of CDCA8 inhibited HCC cell growth by blocking cell-cycle progression, inducing apoptosis. Next generation sequencing (NGS) expression analysis of CDCA8 knockdown signature showed that CDCA8 blockade caused anti-proliferative effects. These effects were also associated with dysregulation of CDCA8-regulated genes that control cell cycle and apoptosis. Anti-proliferative effects were driven by a subset of molecular alterations including the upregulation of ATF3 and GADD34, whereas a key regulator of cell growth and invasiveness BGLAP was repressed. Subsequent Western blotting revealed that CDCA8 silencing also decreased the level of pro-caspase 3 and PARP-1, accelerating apoptotic signaling in HCC cells. Taken together, these findings offer a preclinical proof-of-concept that CDCA8 can be a promising molecular target for systemic therapy of HCC.