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.