Rewiring drug-activated p53-regulatory network from suppressing to promoting tumorigenesis

Many of oncogenes and tumor suppressor genes have been found to exert variable and even opposing roles in different kinds of tumors or at different stages of cancer development. Here we showed that tumorigenic potential of mouse embryonic carcinoma P19 cells cultured in adherent plates (attached-P19-cells) was suppressed by a chemotherapeutic agent, 5-aza-2-deoxycytidine (ZdCyd), whereas the higher pro-tumorigenicity of P19 cells growing in suspension (detached-P19-cells) was generated by the ZdCyd treatment. Surprisingly, p53 activity was highly up-regulated by ZdCyd in both growing conditions. By our developed computational approaches, we revealed that there was a significant enrichment of apoptotic pathways in the ZdCyd-induced p53-dominant gene-regulatory network in attached P19 cells, whereas the pro-survival genes were significantly enriched in the ZdCyd-induced p53 network in detached P19 cells. The proteinprotein interaction network of the ZdCyd-treated detached P19 cells was significantly different from that of ZdCyd-treated attached P19 cells. On the other hand, inhibition of p53 expression by siRNA suppressed the ZdCyd-induced tumorigenesis of detached P19 cells, suggesting that the ZdCyd-activated p53 plays oncogenic function in detached P19 cells. Taken together, these results indicate a context-dependent role for the ZdCyd-activated p53-dominant network in tumorigenesis.