Targeting the Chromosomal Passenger Complex Subunit INCENP Induces Polyploidization, Apoptosis, and Senescence in Neuroblastoma.

Abstract

Chromosomal passenger complex (CPC) has been demonstrated to be a potential target of cancer therapy by inhibiting Aurora B or survivin in different types of cancer including neuroblastoma. However, chemical inhibition of either Aurora B or survivin does not target CPC specifically due to off-target effects or CPC-independent activities of these two components. In a previous chromatin-focused siRNA screen, we found that neuroblastoma cells were particularly vulnerable to loss of <i>INCENP</i>, a gene encoding a key scaffolding component of the CPC. In this study, INCENP was highly expressed by neuroblastoma cells, and its expression decreased following retinoic acid-induced neuroblastoma differentiation. Elevated levels of INCENP were significantly associated with poor prognosis in primary tumors of neuroblastoma patients with high-risk disease. Genetic silencing of INCENP reduced the growth of both <i>MYCN</i>-wild-type and <i>MYCN</i>-amplified neuroblastoma cell lines <i>in vitro</i> and decreased the growth of neuroblastoma xenografts <i>in vivo</i>, with significant increases in murine survival. Mechanistically, INCENP depletion suppressed neuroblastoma cell growth by inducing polyploidization, apoptosis, and senescence. In most neuroblastoma cell lines tested <i>in vitro</i>, apoptosis was the primary cell fate after INCENP silencing due to induction of DNA damage response and activation of the p53-p21 axis. These results confirm that CPC is a therapeutic target in neuroblastoma, and targeting INCENP is a novel way to disrupt the activity of CPC and inhibit tumor progression in neuroblastoma. SIGNIFICANCE: Dysregulation of INCENP contributes to neuroblastoma tumorigenesis and targeting INCENP presents a novel strategy to disrupt the activity of chromosomal passenger complex and inhibit neuroblastoma progression.