A positive feedback signaling loop between ATM and the vitamin D receptor is critical for cancer chemoprevention by vitamin D
Menée sur un modèle murin, cette étude montre que l'effet chimiopréventif de la vitamine D sur la tumorigenèse implique une boucle de régulation positive entre les protéines ATM et le récepteur de la vitamine D
Both epidemiological and laboratory studies have demonstrated the chemopreventive effects of 1-alpha,25- dihydroxyvitamin D3 (1,25-VD) in tumorigenesis. However, understanding remains incomplete concenrning the molecular mechanism by which 1,25-VD prevents tumorigenesis. In this study, we used an established mouse model of chemical carcinogenesis to investigate how 1,25-VD prevents malignant transformation. In this model, 1,25-VD promoted expression of the DNA repair genes RAD50 and ATM, both of which are critical for mediating the signaling responses to DNA damage. Correspondingly, 1,25-VD protected cells from genotoxic stress and growth inhibition by promoting double strand break DNA repair. Depletion of the vitamin D receptor (VDR) reduced these genoprotective effects and drove malignant transformation that could not be prevented by 1,25-VD, defining an essential role for VDR in mediating the anti-cancer effects of 1,25-VD. Notably, genotoxic stress activated ATM and VDR through phosphorylation of VDR. Mutations in VDR at putative ATM phosphorylation sites impaired the ability of ATM to enhance VDR transactivation activity, diminishing 1,25- VD-mediated induction of ATM and RAD50 expression. Together, our findings identify a novel vitamin D-mediated chemopreventive mechanism involving a positive feedback loop between the DNA repair proteins ATM and VDR.