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The TP53 tumor suppressor pathway is abrogated by  TP53  mutations in the majority of human cancers. Increased levels of wild-type TP53 in aggressive neuroblastomas appear paradox but are tolerated by tumor cells due to co-activation of the TP53 ubiquitin ligase, MDM2. The role of the MDM2 antagonist, p14 ARF , in controlling the TP53-MDM2 balance in neuroblastoma is unresolved. In the present study, we show that conditional p14 ARF  expression substantially suppresses viability, clonogenicity and anchorage-independent growth in  p14 ARF  -deficient or  MYCN -amplified neuroblastoma cell lines. Furthermore, ectopic 14 ARF  expression induced accumulation of cells in the G1 phase and apoptosis, which was paralleled by accumulation of TP53 and its targets. Comparative genomic hybridization analysis of 193 primary neuroblastomas detected one homozygous deletion of  CDKN2A  (encoding both p14 ARF  and p16 INK4A ) and heterozygous loss of  CDKN2A  in 22% of tumors. Co-expression analysis of  p14 ARF   and its transactivator, E2F1, in a set of 68 primary tumors revealed only a weak correlation, suggesting that further regulatory mechanisms govern  p14 ARF   expression in neuroblastomas. Intriguingly, analyses utilizing chromatin immunoprecipitation revealed different histone mark-defined epigenetic activity states of  p14 ARF   in neuroblastoma cell lines that correlated with endogenous  p14 ARF   expression but not with episomal  p14 ARF   promoter reporter activity, indicating that the native chromatin context serves to epigenetically repress  p14 ARF   in neuroblastoma cells. Collectively, the data pinpoint p14 ARF  as a critical factor for efficient TP53 response in neuroblastoma cells and assign p14 ARF  as a neuroblastoma suppressor candidate that is impaired by genomic loss and epigenetic repression.

human molecular genetics

Low  p14 ARF   expression in neuroblastoma cells is associated with repressed histone mark status, and enforced expression induces growth arrest and apoptosis