title: Vitamin D receptor as a master regulator of the c-MYC/MXD1 network.
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.
authors.affiliation: Department of Medicine, McGill University, Montreal, QC, Canada H3G 1Y6.
authors.forename: Reyhaneh
authors.initials: R
authors.lastname: Salehi-Tabar
authors.forename: Loan
authors.initials: L
authors.lastname: Nguyen-Yamamoto
authors.forename: Luz E
authors.initials: LE
authors.lastname: Tavera-Mendoza
authors.forename: Thomas
authors.initials: T
authors.lastname: Quail
authors.forename: Vassil
authors.initials: V
authors.lastname: Dimitrov
authors.forename: Beum-Soo
authors.initials: BS
authors.lastname: An
authors.forename: Leon
authors.initials: L
authors.lastname: Glass
authors.forename: David
authors.initials: D
authors.lastname: Goltzman
authors.forename: John H
authors.initials: JH
authors.lastname: White
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D002117:Calcitriol / Q000378:metabolism* / Q000494:pharmacology; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism; D000073979:F-Box-WD Repeat-Containing Protein 7; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D055550:Protein Stability / Q000187:drug effects; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis* / Q000235:genetics; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D012867:Skin / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002117:Calcitriol; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; D011495:Histone-Lysine N-Methyltransferase; D016271:Proto-Oncogene Proteins c-myc; D018167:Receptors, Calcitriol; D012097:Repressor Proteins; D044767:Ubiquitin-Protein Ligases; C513272:Fbxw7 protein, mouse; C499479:Mad protein, mouse; C489428:Myc protein, mouse; C529566:KMT5a protein, mouse