The down-regulation of the human MYC gene by the nuclear hormone 1alpha,25-dihydroxyvitamin D3 is associated with cycling of corepressors and histone deacetylases.
MYC is a pleiotropic transcription factor that coordinates the expression of diverse programs that are together necessary for the growth and expansion of somatic cells. The nuclear hormone 1alpha,25-dihydroxyvitamin D(3) down-regulates MYC expression, but the exact mechanism is still elusive. We found in RWPE-1 normal human prostate cells that 1alpha,25-dihydroxyvitamin D(3) down-regulates MYC mRNA with a periodicity of 30-90 min. In silico screening of the MYC gene locus identified six putative binding sites [vitamin D response elements (VDREs)] for the vitamin D receptor (VDR). Two of these VDREs efficiently bound VDR-retinoid X receptor heterodimers in vitro, and their genomic regions associated with VDR in RWPE-1 cells. Gene-specific small inhibitory RNA silencing indicated that basal MYC mRNA expression, as well as its down-regulation, depended on the exchange factor TBL1X (transducer beta-like 1, X-linked), the corepressor silencing mediator for retinoid and thyroid hormone receptor, and histone deacetylases (HDACs) 2, 6, and 11. Assaying the association of these five proteins with the VDRE-containing genomic regions of the MYC gene locus showed characteristic ligand-dependent profiles of TBL1X, silencing mediator for retinoid and thyroid hormone receptor, HDAC6, and HDAC11, in particular on an evolutionarily conserved VDRE. In conclusion, our data suggest that dynamically composed protein complexes that dock via VDR to the two VDREs may explain the repression of the MYC gene.
Toropainen
Sari
S
Department of Biosciences, University of Eastern Finland, FIN-70211 Kuopio, Finland.
Väisänen
Sami
S
Heikkinen
Sami
S
Carlberg
Carsten
C
D002117:Calcitriol / Q000378:metabolism*; D002478:Cells, Cultured; D056970:Co-Repressor Proteins / Q000378:metabolism*; D015536:Down-Regulation; D056464:Histone Deacetylase 2 / Q000378:metabolism; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D011485:Protein Binding; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis*; D015293:Transducin / Q000378:metabolism*; D030181:Vitamin D Response Element
D056970:Co-Repressor Proteins; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; C119542:TBL1X protein, human; C462506:HDAC11 protein, human; C533423:HDAC2 protein, human; C433811:HDAC6 protein, human; D056464:Histone Deacetylase 2; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; D015293:Transducin; D002117:Calcitriol