C/ebpα represses the oncogenic Runx3–Myc axis in p53-deficient osteosarcoma development

Abstract

Osteosarcoma (OS) is characterized by TP53 mutations in humans. In mice, loss of p53 triggers OS development, and osteoprogenitor-speci c p53-deleted mice are widely used to study the process of osteosarcomagenesis. However, the molecular mechanisms underlying the initiation or progression of OS following or parallel to p53 inactivation remain largely unknown. Here, we examined the role of transcription factors involved in adipogenesis (adipo-TFs) in p53-de cient OS and identi ed a novel tumor suppressive molecular mechanism mediated by C/ebpα. C/ebpα speci cally interacts with Runx3, a p53 de ciency-dependent oncogene, and, in the same manner as p53, decreases the activity of the oncogenic axis of OS, Runx3-Myc, by inhibiting Runx3 DNA binding. The identi cation of a novel molecular role for C/ebpα in p53-de cient osteosarcomagenesis underscores the importance of the Runx-Myc oncogenic axis as a therapeutic target for OS.

Myc upregulates Ggct, γ-glutamylcyclotransferase to promote development ofp53-deficient osteosarcoma

“…Previously, we described the oncogenic role of Runx3-Myc or Runx1-Myc axes in development of p53 -defiecient OS 7–9 or lymphoma 32 , respectively. In both cases, oncogenic Runx transcription factors upregulate Myc in the p53 -deficient context 33 ; thus it is possible that Runx3 upregulates Ggct.…”

“…Correlation analysis ( GGCT vs. MYC ) was performed using Spearman’s correlation method. RNA-seq data from a previous study 9 , which were generated from MSCs and mOS cells isolated from three individual OS mice and submitted to DDJB sequence read archive with the accession number DRA012931, were used. Differential expression analysis of hOB versus hOS and MSCs versus mOS cells, was performed using edgeR, and the results were used to draw heatmaps.…”

“…In mice, loss of p53 in osteoprogenitor or mesenchymal stromal cells (MSCs) is sufficient to trigger osteosarcomagenesis; this was well-documented using the Osterix (Osx) / Sp7 -Cre; p53 fl/fl mouse model 5,6 . In a series of previous studies 7–9 , we identified a vital oncogenic axis comprising Runx3, a member of Runx family of transcription factors, and c-Myc (Myc), a pivotal tumor-promoting factor in OS 10 . In the absence of p53, Runx3 aberrantly upregulates Myc in human and mouse OS cells 7 .…”