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C/EBPβ deletion in oncogenic Ras skin tumors is a synthetic lethal event.
- Source :
-
Cell death & disease [Cell Death Dis] 2018 Oct 15; Vol. 9 (11), pp. 1054. Date of Electronic Publication: 2018 Oct 15. - Publication Year :
- 2018
-
Abstract
- 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-β (C/EBPβ), 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/EBPβ 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/EBPβ-deleted skin did not. These results indicate that the deletion of C/EBPβ de-represses p53 in oncogenic Ras tumors but not in normal wild-type Ras keratinocytes, and that C/EBPβ is essential for survival of oncogenic Ras tumors. Co-deletion of C/EBPβ 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/EBPβ for their survival. RNAseq data analysis of regressing tumors deleted of C/EBPβ 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/EBPβ in oncogenic Ras skin tumors is a synthetic lethal event, making it a promising target for future potential anticancer therapies.
- Subjects :
- 9,10-Dimethyl-1,2-benzanthracene administration & dosage
Animals
Apoptosis drug effects
Apoptosis genetics
CCAAT-Enhancer-Binding Protein-beta deficiency
Cell Differentiation
Cell Transformation, Neoplastic metabolism
Cell Transformation, Neoplastic pathology
Genes, Lethal
Keratinocytes drug effects
Keratinocytes metabolism
Keratinocytes pathology
Mice
Mice, Knockout
Receptors, Death Domain genetics
Receptors, Death Domain metabolism
Signal Transduction
Skin drug effects
Skin metabolism
Skin pathology
Skin Neoplasms chemically induced
Skin Neoplasms metabolism
Skin Neoplasms pathology
Tetradecanoylphorbol Acetate administration & dosage
Tetradecanoylphorbol Acetate analogs & derivatives
Tumor Suppressor Protein p53 genetics
Tumor Suppressor Protein p53 metabolism
ras Proteins metabolism
CCAAT-Enhancer-Binding Protein-beta genetics
Cell Transformation, Neoplastic genetics
Gene Expression Regulation, Neoplastic
Skin Neoplasms genetics
ras Proteins genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2041-4889
- Volume :
- 9
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Cell death & disease
- Publication Type :
- Academic Journal
- Accession number :
- 30323292
- Full Text :
- https://doi.org/10.1038/s41419-018-1103-y