A positive feedback signaling loop between ATM and the vitamin D receptor is critical for cancer chemoprevention by vitamin D

Huei Ju Ting, Sayeda Yasmin-Karim, Shian Jang Yan, Jong Wei Hsu, Tzu Hua Lin, Weisi Zeng, James Messing, Tzong Jeng Sheu, Bo Ying Bao, Willis X. Li, Edward Messing, Yi Fen Lee

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33 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)958-968
Number of pages11
JournalCancer Research
Volume72
Issue number4
DOIs
Publication statusPublished - 2012 Feb 15

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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    Ting, H. J., Yasmin-Karim, S., Yan, S. J., Hsu, J. W., Lin, T. H., Zeng, W., Messing, J., Sheu, T. J., Bao, B. Y., Li, W. X., Messing, E., & Lee, Y. F. (2012). A positive feedback signaling loop between ATM and the vitamin D receptor is critical for cancer chemoprevention by vitamin D. Cancer Research, 72(4), 958-968. https://doi.org/10.1158/0008-5472.CAN-11-0042