p53 promotes Fas repression during tumor growth and progression

Although p53 inactivation is implicated in tumor progression, it is clear that tumor cells that possess transcriptionally functional p53 can also be resistant to diverse apoptotic stimuli. In a survey of genetically matched tumor cell lines that were either wild-type or null for their p53 status we studied the contribution of Fas in promoting this phenomenon. We report that cells with wild-type p53 express increased basal levels of Fas and FasL and are much more sensitive to Fas-mediated cell death than cells lacking p53. Furthermore, we report that DNA damage induces Fas and FasL in cells with wild-type p53 whereas this response is impaired in cells lacking p53 function. Fas expression and induction were transcriptionally repressed in transformed cells with wild-type p53 with increasing passage, whereas other p53 downstream targets and functions such as p21 inducibility and cell cycle arrest, remained intact. Fas repression was found to be due to transcriptional silencing of the Fas gene that was relieved by treatment with the histone deacetylase inhibitor, Trichostatin A. Thus, cells with wild-type p53 were found to be sensitized to FasL-mediated killing, and growth in culture selectively repressed their expression of Fas as a means of evading Fasmediated cell death. The question thus arose if Fas repression allowed for growth of p53 wild-type tumors in vivo and whether restoration of Fas could inhibit tumor growth.;To address these issues, we altered Fas levels of p53 wild-type and null cells either genetically by retrovirally transfecting them with Fas-regulating constructs or pharmacologically with Trichostatin A, to relieve p53-dependent Fas repression. Alteration of Fas levels indeed greatly affected tumor growth. Specifically, genetic restoration of Fas to late-passage p53 wild-type MEFs greatly inhibited in vivo growth. Remarkably, pharmacological restoration of Fas to these late-passage cells with Trichostatin A completed prevented tumor growth in vivo. These data provide clear evidence that p53's modulation of Fas determines tumor growth and progression in vivo. In addition, our findings demonstrate the potential efficacy of the use of histone deacetylase inhibitors as adjuvant therapy in treatment of apoptotically-resistant p53 wild-type tumors in the clinical setting.