A positive feedback signaling loop between ATM and the vitamin D receptor is critical for cancer chemoprevention by vitamin D.
Both epidemiologic and laboratory studies have shown the chemopreventive effects of 1α,25-dihydroxyvitamin D(3) (1,25-VD) in tumorigenesis. However, understanding of the molecular mechanism by which 1,25-VD prevents tumorigenesis remains incomplete. 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 anticancer 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.
Department of Urology, University of Rochester, Rochester, New York, USA.
Huei-Ju
HJ
Ting
Sayeda
S
Yasmin-Karim
Shian-Jang
SJ
Yan
Jong-Wei
JW
Hsu
Tzu-Hua
TH
Lin
Weisi
W
Zeng
James
J
Messing
Tzong-Jeng
TJ
Sheu
Bo-Ying
BY
Bao
Willis X
WX
Li
Edward
E
Messing
Yi-Fen
YF
Lee
D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D017766:Acid Anhydride Hydrolases; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics*; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics*; D008297:Male; D008770:Methylnitrosourea; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009369:Neoplasms / Q000139:chemically induced / Q000517:prevention & control*; D018384:Oxidative Stress / Q000235:genetics; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D020239:Receptor Cross-Talk; D018167:Receptors, Calcitriol / Q000378:metabolism*; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D014807:Vitamin D / Q000494:pharmacology*
D018528:ATP-Binding Cassette Transporters; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D018167:Receptors, Calcitriol; D025521:Tumor Suppressor Proteins; D014807:Vitamin D; D008770:Methylnitrosourea; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; D017766:Acid Anhydride Hydrolases; C495198:Rad50 protein, mouse