# Nuclear and non-nuclear functions of NKX3.1 in suppression of prostate cancer

> **NIH CA R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2026 · $546,133

## Abstract

Project Summary/Abstract
 Our studies will investigate mechanisms associated with aging-related prostate cancer progression
through our investigations of the prostate-specific homeobox gene NKX3.1. Work by us and others has shown
that NKX3.1 is essential for normal prostate differentiation, whereas its loss promotes prostate cancer during
aging. NKX3.1 serves as a gatekeeper to protect the prostate epithelium from cancer-promoting insults including
oxidative stress and inflammation. Conversely, NKX3.1 loss abrogates such protection, thereby accelerating
cancer progression. Our recent studies and new Preliminary data show that the traditional functions of NKX3.1
as a nuclear transcription factor are augmented by non-nuclear functions that are also required for suppression
of prostate cancer. Thus, in normal contexts, NKX3.1 is localized to the nucleus where it regulates nuclear target
genes. However, in conditions of oxidative stress, NKX3.1 also becomes localized to mitochondria, where it
regulates mitochondrial genes essential for oxidative phosphorylation (OXPHOS). Our Preliminary data further
show that the consequences of NKX3.1 loss are compounded as cells acquire mitochondrial mutations, leading
to aging-associated acceleration of prostate cancer. In particular, our analyses of mouse models having loss of
function of Nkx3.1 combined with a defective PolgA gene that renders mutated mitochondrial DNA (Nkx3.1;
PolgA mutant mice) reveals aging-related acceleration of prostate cancer with evident mitochondrial dysfunction,
reduced OXPHOS activity, and hallmarks of aging, including cellular senescence and telomere attrition.
 Thus, our studies will examine the hypothesis that suppression of prostate cancer by NKX3.1 requires
its nuclear and non-nuclear functions, and that NKX3.1 loss synergizes with mitochondrial dysfunction to promote
prostate cancer during aging. Aim 1 will investigate the nuclear and non-nuclear functions of NKX3.1 in prostate
cancer by leveraging

## Key facts

- **NIH application ID:** 11304541
- **Project number:** 5R01CA300337-02
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Cory  Abate-Shen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** CA
- **Fiscal year:** 2026
- **Award amount:** $546,133
- **Award type:** 5
- **Project period:** 2025-04-01T00:00:00 → 2030-03-31T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11304541

## Citation

> US National Institutes of Health, RePORTER application 11304541, Nuclear and non-nuclear functions of NKX3.1 in suppression of prostate cancer (5R01CA300337-02). Retrieved via AI Analytics 2026-06-26 from https://api.ai-analytics.org/grant/nih/11304541. Licensed CC0.

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