# Mechanisms of metabolic stress-induced transcriptional regulation in prostate cancer

> **NIH NIH R01** · ROSWELL PARK CANCER INSTITUTE CORP · 2022 · $354,472

## Abstract

Metastatic prostate cancer (PCa) remains a major clinical challenge. Although androgen deprivation therapy
(ADT) is effective in treating PCa, majority of the patients quickly develop resistance to therapy and the tumor
relapses as hormone refractory castration-resistant prostate cancer (CRPC). Men with CRPC frequently
progress to an aggressive lethal disease that metastasizes to bones and other visceral organs accounting for
high morbidity and mortality. Transcriptional activation of steroid receptor coactivator-2 (SRC-2; also known as
NCOA2/TIF2/GRIP1) plays a critical role in the pathogenesis of PCa by driving a metabolic switch towards de
novo fatty acid biosynthesis. Although increased lipogenesis is a known hallmark of hormone refractory PCa
progression, it is less clear how mitochondrial enzymes communicate with nuclear receptor coregulators to
rapidly fuel and support fat biosynthesis. Our preliminary findings indicate that sustained activity of mitochondrial
aconitase (ACO2) enzyme is critical for regulating citrate synthesis. We found that acetylation of ACO2 is
essential for enzyme functions, which is negatively regulated by sirtuin-3 (SIRT3). In human prostate cancer
patients, SIRT3 expression is repressed and increased expression of SRC-2 with concomitant reduction of
SIRT3 was found to be a genetic hallmark in metastatic PCa. Based on these findings, we hypothesize that the
transcriptional coregulator SRC-2 drives the nuclear-mitochondrial regulatory axis by repressing tumor
suppressor SIRT3 thus promoting prostate tumor survival and metastasis competence. So our objectives in this
proposal are (1) to investigate the mechanisms regulating sustained activation of mitochondrial ACO2 to promote
lipogenesis, (2) define the role of nuclear receptor coregulator SRC-2 regulating SIRT3 expression, and (3)
evaluate the impact of this nuclear-mitochondrial regulatory axis on prostate tumor survival and adaptation
leading to bone colonization and growth. Our study will uncover molecular links between mitochondrial
metabolism and transcriptional regulation that enables hormone refractory PCa adaptation, survival and
ultimately metastatic competency.

## Key facts

- **NIH application ID:** 10376802
- **Project number:** 5R01CA252092-02
- **Recipient organization:** ROSWELL PARK CANCER INSTITUTE CORP
- **Principal Investigator:** Subhamoy Dasgupta
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $354,472
- **Award type:** 5
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10376802

## Citation

> US National Institutes of Health, RePORTER application 10376802, Mechanisms of metabolic stress-induced transcriptional regulation in prostate cancer (5R01CA252092-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10376802. Licensed CC0.

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