Transcriptional regulation by RUNX2

RUNX2 expression is regulated by estrogen signaling, and RUNX2 is implicated in breast cancer development and metastasis (reviewed in Wysokinski et al. 2014). Besides estrogen receptor alpha (ESR1) and estrogen-related receptor alpha (ERRA), RUNX2 transcription is also regulated by TWIST1 (Yang, Yang et al. 2011), glucocorticoid receptor (NR3C1), NKX3-2 (BAPX1), DLX5 and MSX2. RUNX2 can autoregulate, by directly inhibiting its own transcription. Several E3 ubiquitin ligases target RUNX2 for proteasome-mediated degradation: STUB1 (CHIP), SMURF1, WWP1, and SKP2. Besides formation of RUNX2:CBFB heterodimers, transcriptional activity of RUNX2 is regulated by binding to a number of other transcription factors, for example SOX9 (Zhou et al. 2006, TWIST1 and RB1.

RUNX2 regulates expression of several genes implicated in cell migration during normal development and bone metastasis of breast cancer cells. RUNX2 stimulates transcription of the ITGA5 gene, encoding Integrin alpha 5 and the ITGBL1 gene, encoding Integrin beta like protein 1. RUNX2 mediated transcription of the MMP13 gene, encoding Colagenase 3 (Matrix metalloproteinase 13), is stimulated by AKT mediated phosphorylation of RUNX2. RUNX2 is implicated in positive regulation of AKT signaling by stimulating expression of AKT-activating TORC2 complex components MTOR and RICTOR, which may contribute to survival of breast cancer cells.

RUNX2 inhibits CDKN1A transcription, thus preventing CDKN1A-induced cell cycle arrest. Phosphorylation of RUNX2 by CDK4 in response to high glucose enhances RUNX2-mediated repression of the CDKN1A gene in endothelial cells. In mice, Runx2-mediated repression of Cdkn1a may contribute to the development of acute myeloid leukemia (AML). RUNX2 can stimulate transcription of the LGALS3 gene, encoding Galectin-3. Galectin 3 is expressed in myeloid progenitors and its levels increase during the maturation process (Le Marer 2000).

For a review of RUNX2 function, please refer to Long 2012 and Ito et al. 2015.