The oncogenic Runx3–Myc axis definesp53-deficient osteosarcomagenesis

Abstract

Osteosarcoma (OS) in human patients is characterized by genetic alteration of TP53. Osteoprogenitor-specific p53-deleted mice (OS mice) have been widely used to study the process of osteosarcomagenesis. However, the molecular mechanisms responsible for the development of OS upon p53 inactivation remain largely unknown. In this study, we detected prominent RUNX3/Runx3 expression in human and mouse p53-deficient OS. Myc was aberrantly upregulated by Runx3 via mR1, a consensus Runx site in the Myc promoter, in a manner dependent on p53 deficiency. Reduction of the Myc level by disruption of mR1 or Runx3 knockdown decreased the tumorigenicity of p53-deficient OS cells and effectively suppressed OS development in OS mice. Furthermore, Runx inhibitors exerted therapeutic effects on OS mice. Together, these results show that p53 deficiency promotes osteosarcomagenesis in human and mouse by allowing Runx3 to induce oncogenic Myc expression.

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][8][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][8][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 .…”