p53 Deficiency-Dependent Oncogenicity of Runx3

Abstract

The RUNX transcription factors are frequently dysregulated in human cancers, suggesting their potential as attractive targets for drug treatment. However, all three transcription factors have been described as both tumor suppressors and oncogenes, indicating the need to determine their molecular mechanisms of action. Although RUNX3 has long been considered a tumor suppressor in human cancers, several recent studies have shown that RUNX3 is upregulated during the development or progression of various malignant tumors, suggesting it may act as a “conditional” oncogene. Resolving this paradox and understanding how a single gene can exhibit both oncogenic and tumor-suppressive properties is essential for successful drug targeting of RUNX. This review describes the evidence for the activities of RUNX3 in human cancer and proposes an explanation for the duality of RUNX3 involving the status of p53. In this model, p53 deficiency causes RUNX3 to become oncogenic, leading to aberrant upregulation of MYC.

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

“…The Therapeutically Applicable Research to Generate Effective Treatments (TARGET) cohort was used to evaluate changes in expression of genes encoding the enzymes. Inactivation of p53 is critical for development and progression of OS in both humans and mice 8 . Almost all cases (84 of 86) in the TARGET cohort harbored gene alterations of TP53 7 .…”

“…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.…”

“…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 .…”