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

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


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.

Publication types

  • Research Support, N.I.H., Extramural

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 / 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


  • 12-O-tetradecanoylphorbol-1,3-acetate
  • CCAAT-Enhancer-Binding Protein-beta
  • Cebpb protein, mouse
  • Receptors, Death Domain
  • Tumor Suppressor Protein p53
  • 9,10-Dimethyl-1,2-benzanthracene
  • ras Proteins
  • Tetradecanoylphorbol Acetate