We have been studying the processes associated with prostate differentiation and their relationship to prostate cancer through our investigations of the NKX3.1 homeobox gene, which is a master regulator of prostate epithelial specification that protects the prostatic epithelium from assaults associated with cancer initiation, including oxidative stress. Our investigations have now revealed that NKX3.1 defends prostate cells from oxidative stress by regulating gene expression in both the nucleus and mitochondria. We find that, in addition to its expected functions as a transcriptional factor in the nucleus, NKX3.1 also localizes to mitochondria in response to oxidative stress, where it regulates the expression of mitochondrial-encoded genes that control reactive oxygen species (ROS). Thus, we hypothesize that NKX3.1 regulates oxidative stress via its coordinated functions in nuclei and mitochondria, and that these functions are necessary to maintain prostate epithelial differentiation and suppress cancer initiation. Since relatively few nuclear transcriptional regulatory proteins have been shown to function in mitochondria, our studies provide a unique opportunity to understand how a tissue-specific transcription factor can control oxidative stress in different sub- cellular compartments, and the relevance of these activities for cancer.
In Aim 1, we will investigate the functions of NKX3.1 in the nucleus for protection from oxidative stress and promotion of differentiation. We will investigate: (i) nuclear transcriptional regulatory functions of NKX3.1 for protection against oxidative stress; (ii) their relevance for prostate epithelial differentiation and cancer; and (iii) whether and if so how these functions impact mitochondrial function.
In Aim 2, we will investigate novel functions of NKX3.1 in mitochondria. Based on our preliminary data showing that, in response to oxidative stress, NKX3.1 becomes localized to mitochondria where it regulates the expression of mitochondrial-encoded genes, we will investigate: (i) the mechanisms associated with localization of NKX3.1 to mitochondria; (ii) the mechanisms by which NKX3.1 regulates mitochondrial-encoded genes, particularly in comparison with its regulation of nuclear genes; and (iii) the importance of these mitochondrial-specific functions of NKX3.1 for regulation of oxidative stress and cellular differentiation.
In Aim 3, we will complement these mechanistic studies by performing co-clinical studies to evaluate the relevance of regulation of oxidative stress by NKX3.1 for suppression of prostate cancer, and whether these activities can be targeted for cancer prevention using genetically-engineered mouse models and a human prostate tissue organotypic model. Relevance for PAR-17-203: Our proposed studies provide a unique opportunity to elucidate molecular mechanisms that govern the balance between oxidative stress and differentiation and cancer initiation and how these are coordinated between the nucleus and mitochondria.

Public Health Relevance

Understanding the processes involved in cancer initiation will have far-reaching implications for early detection, accurate prognosis, and appropriate intervention. The premise of our research is that elucidating the mechanisms that control normal prostate differentiation will reveal how they go awry in cancer. Our biological and mechanistic investigations of NKX3.1, which is a homeobox gene that promotes normal prostate differentiation and suppresses prostate cancer, have now uncovered novel functions for NKX3.1 in both the nucleus and mitochondria for controlling these cellular processes.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA233176-01
Application #
9626595
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Espey, Michael G
Project Start
2018-12-01
Project End
2023-11-30
Budget Start
2018-12-01
Budget End
2019-11-30
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Pharmacology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032