# Mitochondrial and nuclear functions of NKX3.1 in regulating oxidative stress in prostate cancer

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $387,084

## Abstract

Project Summary/Abstract
 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...

## Key facts

- **NIH application ID:** 9829089
- **Project number:** 5R01CA233176-02
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Cory Abate-Shen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $387,084
- **Award type:** 5
- **Project period:** 2018-12-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9829089

## Citation

> US National Institutes of Health, RePORTER application 9829089, Mitochondrial and nuclear functions of NKX3.1 in regulating oxidative stress in prostate cancer (5R01CA233176-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9829089. Licensed CC0.

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