Haploinsufficient prostate tumor suppression by Nkx3.1: a role for chromatin accessibility in dosage-sensitive gene regulation.
Transcription factor haploinsufficiency plays a role in the pathogenesis of many diseases, including cancer. In a mouse model of prostate tumor initiation, loss of a single allele of the tumor suppressor Nkx3.1 stochastically inactivates the expression of a class of dosage-sensitive target genes. Here we show that dosage sensitivity is associated with the differential histone H3/H4 acetylation states of Nkx3.1 target genes. When histone acetylation is induced in Nkx3.1+/- mouse prostates with the histone deacetylase inhibitor Trichostatin A, Nkx3.1 can bind to and reactivate the expression of dosage-sensitive target genes. We incorporated our findings into a mathematical model that entails the association of Nkx3.1 with histone acetyltransferase activity. Subsequent experiments indicate that Nkx3.1 associates with and recruits the histone acetyltransferase p300/CREB-binding protein-associated factor to chromatin. Finally, we demonstrate a role for the dosage-sensitive target gene intelectin/omentin in suppressing prostate tumorigenicity. Our results reveal how the interplay between transcription factor dosage and chromatin affects target gene expression in tumor initiation.
Mogal
Ashish P
AP
Department of Pathology, Vanderbilt University Medical Center, Nashville 37232, USA.
van der Meer
Riet
R
Crooke
Philip S
PS
Abdulkadir
Sarki A
SA
D000107:Acetylation; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002843:Chromatin / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects / Q000235:genetics; D004195:Disease Models, Animal; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000096:biosynthesis* / Q000235:genetics; D006877:Hydroxamic Acids / Q000494:pharmacology; D037102:Lectins / Q000096:biosynthesis / Q000235:genetics; D019656:Loss of Heterozygosity / Q000187:drug effects / Q000235:genetics; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008954:Models, Biological; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis* / Q000235:genetics; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism
D002843:Chromatin; D006657:Histones; D018398:Homeodomain Proteins; D006877:Hydroxamic Acids; C115657:Itlnb protein, mouse; D037102:Lectins; C102837:Nkx3-1 protein, mouse; D011500:Protein Synthesis Inhibitors; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C012589:trichostatin A; D051548:Histone Acetyltransferases; D050880:p300-CBP Transcription Factors