2018 journal article

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

Cell Death & Disease, 9(11).

By: Z. Messenger, J. Hall, D. Jima, J. House, H. Tam, D. Tokarz n, R. Smart*

co-author countries: United States of America 🇺🇸
MeSH headings : 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 / drug effects; Skin / metabolism; Skin / pathology; Skin Neoplasms / chemically induced; Skin Neoplasms / genetics; 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 / genetics; ras Proteins / metabolism
Source: Crossref
Added: February 21, 2020

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.