Regulation of BIRC5 and its isoform BIRC5-2B in neuroblastoma

We analysed the expression of BIRC5 and BIRC5-2B in primary neuroblastoma (NB) tumors and NB model systems. In tumors, overexpression of BIRC5 correlated closely with its isoform BIRC5-2B. Expression of both transcripts was stage-dependent, associated with poor prognosis and with the expression of the transcription factor E2F1. In cell culture, we identified BIRC5 as a direct transcriptional target of activating E2Fs, primarily when p21Cip1 and p27Kip1, two other E2F1 targets, are strongly suppressed. Deregulated MYCN indirectly induces BIRC5 through suppression of CDKN1A/p21Cip1 and induction of Skp2, which in turn favors the degradation of p27Kip1. In addition, increased BIRC5 protein stability via phosphorylation is mediated by expression of E2F targets such as CDC2. In line with this, selective knock down of CDC2 inhibited BIRC5 abundance and suppressed its anti-apoptotic activities. We conclude that BIRC5 is induced via a functional cooperation between MYCN and E2F1.