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

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.

The Mir181ab1 cluster promotes KRAS-driven oncogenesis and progression in lung and pancreas

“…Lastly, we focused on those TFs that had been previously linked to RAS signaling (Cebpα, Cebpβ, Cmyb, Evi1, Meis1, The similar expression pattern of Gata3 and miR181a/miR181b, and the presence of regulatory elements in the Mir181ab1 promoter suggested that miR181a1 and miR181b1 could be regulated by Gata3. To substantiate this potential association, further analysis of GATA3 expression was done in immortalized lung epithelial cells expressing Gata2, Gata3, and Foxa2) (51)(52)(53)(54)(55)(56)(57)(58). Quantitative PCR (qPCR) analysis of the TFs revealed upregulation of Gata3 in both mouse lung and pancreatic cancer cell lines after TGF-β treatment for 3 hours ( Figure 9C), while no consistent upregulation in the 2 cell lines was found for the remaining TFs (Supplemental Figure 6, C and D).…”

RAS induced senescence of skin keratinocytes is mediated through Rho‐associated protein kinase (ROCK)

“…Therefore, it is likely a yet undisclosed TGF-β mechanism contributed to the anti-senescent activity of Y-27632. Additional reports of pathways associated with RAS induced senescence in keratinocytes include ID1, 37 CEBP-β, 38 ΔNp63α, 39,40 PRAK, 41 PPARβ/δ, 42 and NF-κB. 43 It is not surprising that multiple regulatory pathways are involved as essential factors in the struggle between proliferation and senescence in keratinocytes transformed by oncogenic RAS since this struggle is a critical protective response in tumor formation.…”

Targeting IKKε in Androgen-Independent Prostate Cancer Causes Phenotypic Senescence and Genomic Instability

“…In addition to its key function in pro-inflammatory cytokine secretion, C/EBP- has a role in DNA damage resolution since it regulates the transcription of genes involved in DNA repair, such as BRCA1/2, ATM or Rad51 [54][55][56]. Importantly, IKK also plays a role in protecting cells from DNA-damage-induced cell death [57].…”