Vitamin D receptor as a master regulator of the c-MYC/MXD1 network
Open Access
- 29 October 2012
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 109 (46), 18827-18832
- https://doi.org/10.1073/pnas.1210037109
Abstract
Vitamin D signaling regulates cell proliferation and differentiation, and epidemiological data suggest that it functions as a cancer chemopreventive agent, although the underlying mechanisms are poorly understood. Vitamin D signaling can suppress expression of genes regulated by c-MYC, a transcription factor that controls epidermal differentiation and cell proliferation and whose activity is frequently elevated in cancer. We show through cell- and animal-based studies and mathematical modeling that hormonal 1,25-dihydroxyvitamin D (1,25D) and the vitamin D receptor (VDR) profoundly alter, through multiple mechanisms, the balance in function of c-MYC and its antagonist the transcriptional repressor MAD1/MXD1. 1,25D inhibited transcription of c-MYC–regulated genes in vitro, and topical 1,25D suppressed expression of c-MYC and its target setd8 in mouse skin, whereas MXD1 levels increased. 1,25D inhibited MYC gene expression and accelerated its protein turnover. In contrast, it enhanced MXD1 expression and stability, dramatically altering ratios of DNA-bound c-MYC and MXD1. Remarkably, F-box protein FBW7, an E3-ubiquitin ligase, controlled stability of both arms of the c-MYC/MXD1 push–pull network, and FBW7 ablation attenuated 1,25D regulation of c-MYC and MXD1 turnover. Additionally, c-MYC expression increased upon VDR knockdown, an effect abrogated by ablation of MYC regulator β-catenin. c-MYC levels were widely elevated in vdr−/− mice, including in intestinal epithelium, where hyperproliferation has been reported, and in skin epithelia, where phenotypes of VDR-deficient mice and those overexpressing epidermal c-MYC are similar. Thus, 1,25D and the VDR regulate the c-MYC/MXD1 network to suppress c-MYC function, providing a molecular basis for cancer preventive actions of vitamin D.This publication has 62 references indexed in Scilit:
- The histone methyltransferase Setd8 acts in concert with c-Myc and is required to maintain skinThe EMBO Journal, 2011
- AlleleSeq: analysis of allele‐specific expression and binding in a network frameworkMolecular Systems Biology, 2011
- Cross-regulation of signaling pathways: An example of nuclear hormone receptors and the canonical Wnt pathwayExperimental Cell Research, 2010
- The ubiquitous nature of cancer: the role of the SCFFbw7 complex in development and transformationOncogene, 2010
- Biological determinants of endocrine resistance in breast cancerNature Reviews Cancer, 2009
- c-Myc activates multiple metabolic networks to generate substrates for cell-cycle entryOncogene, 2009
- FOXOs, cancer and regulation of apoptosisOncogene, 2008
- FBW7 ubiquitin ligase: a tumour suppressor at the crossroads of cell division, growth and differentiationNature Reviews Cancer, 2008
- Vitamin D signalling pathways in cancer: potential for anticancer therapeuticsNature Reviews Cancer, 2007
- Vitamin D DeficiencyNew England Journal of Medicine, 2007