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.

Keywords: Runx3; T-cell lymphoma; c-Myc; osteosarcoma; p53.

Figure 1

(A,B) Osx-Cre; p53^fl/fl (OS) mice with heterozygous deletions of Runx3 (OS; Runx3^fl/+ mice) or Myc (OS; Myc^fl/+ mice) or with mR1 (a Runx consensus site, TGCGGT in the Myc promoter) homozygous mutation replaced by the Bgl II site, AGATCT (OS; mR1^m/m mice) show a significantly longer life span (A) and less incidence of OS development than the original OS mice (B). (C) Runx3 heterozygous, Myc heterozygous, or mR1 homozygous mutations produce a similar result, i.e., suppression of Myc in vivo. (A,B) are modified from Otani et al. (2022) [32].

Figure 2

Exogenous RUNX3 upregulates p21 but not MYC in p53-positive U2OS cells, but conversely upregulates MYC but not p21 in p53-negative G292 cells. The data are modified from Otani et al. (2022) [32].

Figure 3

Lck-Cre; p53^fl/fl (LP) mice with heterozygous deletions of Myc (LP; Myc^fl/+ mice) or Runx1 (LP; Runx1^fl/+ mice) show a significantly longer life span than the original LP mice. The data are modified from Date et al. (2022) [53].

Figure 4

p53 status is the contextual determinant of whether Runx3 functions as a tumor-suppressor or an oncogene. (A,B) In p53-positive normal cells, Runx3, whose transcriptional activation is inhibited by p53, acts as a co-activator of p53 in a tumor-suppressive manner and upregulates p21. (C,D) In p53-negative tumor cells, Runx3 is unleashed from p53 and strongly upregulates Myc as an oncogene. In this context, treatment with a Runx inhibitor (AI-10-104; AI) is effective.