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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

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

Authors: Messenger, Zachary J; Hall, Jonathan R; Jima, Dereje D; House, John S; Tam, Hann W; Tokarz, Debra A; Smart, Robert C

Published In Cell Death Dis, (2018 10 15)

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.

PubMed ID: 30323292 Exiting the NIEHS site

MeSH Terms: 9,10-Dimethyl-1,2-benzanthracene/administration & dosage; Animals; Apoptosis/drug effects; Apoptosis/genetics; CCAAT-Enhancer-Binding Protein-beta/deficiency; CCAAT-Enhancer-Binding Protein-beta/genetics*; Cell Differentiation; Cell Transformation, Neoplastic/genetics*; Cell Transformation, Neoplastic/metabolism; Cell Transformation, Neoplastic/pathology; Gene Expression Regulation, Neoplastic*; Genes, Lethal; Keratinocytes/drug effects; Keratinocytes/metabolism; Keratinocytes/pathology; Mice; Mice, Knockout; Receptors, Death Domain/genetics; Receptors, Death Domain/metabolism; Signal Transduction; Skin Neoplasms/chemically induced; Skin Neoplasms/genetics*; Skin Neoplasms/metabolism; Skin Neoplasms/pathology; Skin/drug effects; Skin/metabolism; Skin/pathology; Tetradecanoylphorbol Acetate/administration & dosage; Tetradecanoylphorbol Acetate/analogs & derivatives; Tumor Suppressor Protein p53/genetics; Tumor Suppressor Protein p53/metabolism; ras Proteins/genetics*; ras Proteins/metabolism

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