Abstract
Medulloblastomas are highly malignant, poorly differentiated childhood tumours arising in the cerebellum. These tumors rarely lose TP53, which is the most commonly mutated gene in cancer. Recent work has shown that the basal level of p53 plays an important role in maternal reproduction by maintaining the expression of LIF in the uterus. Since LIF can maintain the undifferentiated state of stem cells we set out to ask if p53 regulates LIF in the human medulloblastoma cell lines DAOY and D283MED. We also used p53-/- and p53+/+ isogenic HCT116 colorectal carcinoma cell lines, already reported to exhibit p53-dependent expression of the LIF D transcript, to establish the extent of p53-dependency for LIF M and T alternative transcripts. Whilst all three known, full-length alternative transcripts are more abundant in p53+/+ cells, the alternative LIF M and T transcripts appear particularly sensitive to p53. In the p53 wild-type medulloblastoma cell line D283MED chromatin immunoprecipitation experiments showed p53 binding to the LIF gene. The mutant p53 expressed in line DAOY did not bind to this region or to the p21(WAF1) p53 binding site. RNA interference against either WIP1 or SIRT1 stabilized p53 and enhanced the transcription of LIF in D283MED cells. Interestingly, siRNA against WIP1 or SIRT1 also induced increased apoptosis in the medulloblastoma line D283MED and, over a longer time period, in DAOY cells. We speculate that suppression of p53 function by combined WIP1-mediated dephosphorylation and SIRT1 deacetylation enables medulloblastoma cell survival but p53-dependent and independent apoptotic pathways remain intact. Thus small molecule inhibitors of SIRT1 may be useful in treatment of medulloblastoma.