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.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-06212007-085438 |
| Date | 21 June 2007 |
| Creators | Mogal, Ashish Popatrao |
| Contributors | Dr. Fritz Parl, Dr. Simon Hayward, Dr. David Head, Dr. Zu-Wen Sun, Dr. Pampee Young |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-06212007-085438/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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