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 (NB). However, chemical inhibition of either Aurora B or Survivin doesn t 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 NB cells were particularly vulnerable to loss of INCENP, a gene encoding a key scaffolding component of the CPC. In this study, INCENP was highly expressed by NB cells and its expression decreased following retinoic acid-induced NB differentiation. Elevated levels of INCENP were significantly associated with poor prognosis in primary tumors of NB patients with high-risk disease. Genetic silencing of INCENP reduced the growth of both MYCN-wild-type (MYCN-WT) and MYCN-amplified (MYCN-amp) NB cell lines in vitro and decreased the growth of NB xenografts in vivo with significant increases in murine survival. Mechanistically, INCENP depletion suppressed NB cell growth by inducing polyploidization, apoptosis and senescence. In most NB cell lines tested in vitro, 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 NB and targeting INCENP is a novel way to disrupt the activity of CPC and inhibit tumor progression in NB.