This project investigates the role of NKX3.1 in protection against DNA damage in the prostate epithelium, which may provide a key mechanism for its function in tumor suppression, NKX3.I is a prostate specific homeobox gene located on 8p21, the target for the most frequent chromosomal loss in human prostate cancer. NKX3.I is also a tumor suppressor for which reduced protein expression is sufficient to deregulate prostate epithelial cell growth and cause Intraepithelial neoplasia;moreover, Nkx3.1 haploinsufficiency results in prostate epithelial dysplasia in mice. Consistent with its role as a tumor suppressor in human prostate cancer, we have shown that an Inactivating mutation In the NKX3.I homeodomain cosegregates with early onset prostate cancer in a prostate cancer family. In recent studies, we have shown that NKX3.1 enhances cell survival after DNA damage and affects the earliest events in recognition of DNA breaks, including formation of YH2AX foci and phosphorylation of ATM. Based on our hypothesis that a key mechanism by which NKX3.1 loss contributes to tumor initiation is through its impact on the DNA damage response, our studies will define the mechanistic role of NKX3.I in the DNA damage response in vitro, as well as its impact on DNA damage in vivo. We also will determine whether NKX3.I mediates the susceptibility of prostate cells to formation of the characteristic TMPRSS2- ERG chromosomal rearrangement that occurs in approximately 50% of prostate cancers. Taken together, our three aims will delineate the role of NKXS.I in the DNA damage response in distinct contexts, thereby providing a comprehensive investigation of this key mechanism of tumor suppression.
In Aim 1, our experiments will define the dynamics of the functional interaction between NKX3.1 and ATM, which occurs within minutes of DNA damage.
In Aim 2, we will determine whether Nkx3.I gene copy number affects the DNA damage response in vivo in the prostate epithelium, and particularly in prostate epithelial stem cells. Finally, in Aim 3, using unique lines of LNCaP cells that we have derived, we will determine whether NKX3.1 affects the frequency of TMPRSS2-ERG gene rearrangements. These proposed studies will be highly integrated with the overall program project. Notably, the experiments in Aim 2 include quantitative immunostaining analyses in collaboration with Core A, the work in Aim 2 on the prostate stem cells will be performed in collaboration with Michael Shen (Project 1), and the entirety of this project is linked to the molecular analyses of Nkx3.1 in cellular senescence by Cory Abate-Shen (Project 2).

Public Health Relevance

Prostate cancer is diagnosed in nearly 200,000 men a year and is responsible for 29,000 deaths annually. Our lab has been the lead proponent of a central role of NKX3.I loss in the earliest stages of prostate cancer initiation. The current project will elucidate a key mechanism of NKX3.1 tumor suppression, namely protection against DNA damage. Our long term goal is to identify mechanisms that will lead to upregulation of NKX3.1 as a strategy for prostate cancer prevention or treatment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA154293-04
Application #
8724936
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Type
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10032
Le Magnen, Clémentine; Dutta, Aditya; Abate-Shen, Cory (2016) Optimizing mouse models for precision cancer prevention. Nat Rev Cancer 16:187-96
Dutta, Aditya; Le Magnen, Clémentine; Mitrofanova, Antonina et al. (2016) Identification of an NKX3.1-G9a-UTY transcriptional regulatory network that controls prostate differentiation. Science 352:1576-80
Zhang, Hailan; Zheng, Tian; Chua, Chee Wai et al. (2016) Nkx3.1 controls the DNA repair response in the mouse prostate. Prostate 76:402-8
Mitrofanova, Antonina; Aytes, Alvaro; Zou, Min et al. (2015) Predicting Drug Response in Human Prostate Cancer from Preclinical Analysis of In Vivo Mouse Models. Cell Rep 12:2060-71
Bowen, Cai; Zheng, Tian; Gelmann, Edward P (2015) NKX3.1 Suppresses TMPRSS2-ERG Gene Rearrangement and Mediates Repair of Androgen Receptor-Induced DNA Damage. Cancer Res 75:2686-98
Shibata, Maho; Shen, Michael M (2015) Stem cells in genetically-engineered mouse models of prostate cancer. Endocr Relat Cancer 22:T199-208
Shen, Michael M (2015) Cancer: The complex seeds of metastasis. Nature 520:298-9
Shen, Michael M (2015) Illuminating the Properties of Prostate Luminal Progenitors. Cell Stem Cell 17:644-6
Song, Liang-Nian; Silva, Jose; Koller, Antonius et al. (2015) The Tumor Suppressor NKX3.1 Is Targeted for Degradation by DYRK1B Kinase. Mol Cancer Res 13:913-22
Lee, Suk Hyung; Shen, Michael M (2015) Cell types of origin for prostate cancer. Curr Opin Cell Biol 37:35-41

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