| First Author | Messenger ZJ | Year | 2018 |
| Journal | Cell Death Dis | Volume | 9 |
| Issue | 11 | Pages | 1054 |
| PubMed ID | 30323292 | Mgi Jnum | J:317894 |
| Mgi Id | MGI:6859985 | Doi | 10.1038/s41419-018-1103-y |
| Citation | Messenger ZJ, et al. (2018) C/EBPbeta deletion in oncogenic Ras skin tumors is a synthetic lethal event. Cell Death Dis 9(11):1054 |
| abstractText | Therapeutic targeting of specific genetic changes in cancer has proven to be an effective therapy and the concept of synthetic lethality has emerged. CCAAT/enhancer-binding protein-beta (C/EBPbeta), a basic leucine zipper transcription factor, has important roles in cellular processes including differentiation, inflammation, survival, and energy metabolism. Using a genetically engineered mouse model, we report that the deletion C/EBPbeta in pre-existing oncogenic Ha-Ras mouse skin tumors in vivo resulted in rapid tumor regression. Regressing tumors exhibited elevated levels of apoptosis and p53 protein/activity, while adjacent C/EBPbeta-deleted skin did not. These results indicate that the deletion of C/EBPbeta de-represses p53 in oncogenic Ras tumors but not in normal wild-type Ras keratinocytes, and that C/EBPbeta is essential for survival of oncogenic Ras tumors. Co-deletion of C/EBPbeta and p53 in oncogenic Ras tumors showed p53 is required for tumor regression and elevated apoptosis. In tumors, loss of a pathway that confers adaptability to a stress phenotype of cancer/tumorigenesis, such as DNA damage, could result in selective tumor cell killing. Our results show that oncogenic Ras tumors display a significant DNA damage/replicative stress phenotype and these tumors have acquired a dependence on C/EBPbeta for their survival. RNAseq data analysis of regressing tumors deleted of C/EBPbeta indicates a novel interface between p53, type-1 interferon response, and death receptor pathways, which function in concert to produce activation of extrinsic apoptosis pathways. In summary, the deletion of C/EBPbeta in oncogenic Ras skin tumors is a synthetic lethal event, making it a promising target for future potential anticancer therapies. |
