Analysis of Nkx3.1 Target Genes in Prostate Cancer

Abstract

This project is focused on understanding the molecular mechanisms of prostate tumor initiation due the loss of the tumor suppressor gene Nkx3.1. Here, we examined the dosage-sensitive and stochastic target gene regulation by Nkx3.1 as a mechanism of haploinsufficient prostate tumor suppression. Our results showed that the dosage-sensitive and insensitive Nkx3.1 target genes are regulated by differential H3/H4 acetylation and Nkx3.1 occupancy in vivo. Our findings underscore the importance of chromatin accessibility in dosage-sensitive target gene regulation by Nkx3.1. We next established the functional significance of dosage-sensitive Nkx3.1 target gene intelectin / omentin in prostate tumorigenesis. We found that intelectin suppresses prostate cell growth in vitro and in vivo suggesting its tumor suppressor-like activity in prostate cancer. In summary, our results provide an example of how a genetic lesion such as haploid loss of the Nkx3.1 tumor suppressor can engender epigenetic changes such as alterations in histone H3/H4 acetylation that selectively inactivate a dosage-sensitive target gene important for suppressing tumorigenicity.