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Cell Death Dis. 2018 Oct 15;9(11):1054. doi: 10.1038/s41419-018-1103-y.

C/EBPβ deletion in oncogenic Ras skin tumors is a synthetic lethal event.

Author information

1
Toxicology Program, Raleigh, NC, USA.
2
Toxicology Program, Raleigh, NC, USA. jrhall@ncsu.edu.
3
Center of Human Health and the Environment, Raleigh, NC, USA. jrhall@ncsu.edu.
4
Department of Biological Sciences, Raleigh, NC, USA. jrhall@ncsu.edu.
5
Center of Human Health and the Environment, Raleigh, NC, USA.
6
Bioinformatics Research Center, Raleigh, NC, USA.
7
Department of Population Health and Pathobiology, North Carolina State University, Raleigh, NC, USA.
8
Toxicology Program, Raleigh, NC, USA. rcsmart@ncsu.edu.
9
Center of Human Health and the Environment, Raleigh, NC, USA. rcsmart@ncsu.edu.
10
Department of Biological Sciences, Raleigh, NC, USA. rcsmart@ncsu.edu.

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.

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