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A Novel Nuclear-Mitochondrial Communication Signal Drives Advanced Prostate Cancer - Beyond the Abstract

Prostate cancer (PCa) is the most common cancer in American men. Even though the 5-year survival rate for localized and regional PCa is 100%, the 5-year survival rate for patients with distant metastasis is only 31%, suggesting there is an urgent need to understand the underlying mechanisms that drive advanced prostate cancer to discover new therapies.1 Dysregulated lipid metabolism is a major hallmark of prostate cancer, which is associated with poor prognosis.2 Major oncogenes of prostate cancer enhance lipid synthesis by increasing the expression of fatty acid biosynthesis enzymes.3 Acetyl-CoA is the precursor molecule for lipid synthesis, which is formed by breaking down citrate. Citrate is produced in the mitochondria and then exported into the cytosol for lipid synthesis. Thus, to support the increased lipid synthesis, mitochondria of the prostate tumors must increase the production of citrate. Although we know several transcriptional factors activate the enzymes to increase lipogenesis, it remains unclear how these nuclear factors communicate with mitochondria to increase citrate synthesis to provide building blocks for lipogenesis.


To address this gap in knowledge, we analyzed the mitochondrial enzymes regulating citrate levels and identified aconitase 2 (ACO2) enzyme activity is essential to support lipogenesis. Genetic deletion of ACO2 in castration-resistant prostate cancer (CRPC) cell lines, an aggressive form of prostate cancer, significantly reduced lipid levels with an eventual reduction in tumor growth in mouse models. In normal prostate epithelial cells, ACO2 enzyme activity is inhibited so that citrate is not oxidized in the mitochondria, and hence can be secreted into the prostatic lumen to support sperm viability.4 However, during prostate cancer progression, ACO2 enzyme is reactivated to meet the increased energy demand of proliferative cancer cells. Since ACO2 is needed to provide a constant supply of citrate for lipid synthesis, we investigated the mechanisms that regulate sustained ACO2 activity. Proteomics studies identified a post-translational modification (PTM) in the form of acetylation on lysine 258 of ACO2 protein, and mutational studies confirmed that lysine 258 acetylation of ACO2 is required for its optimal activity. This made us question whether regulation of ACO2 acetylation could be the missing link that allows nuclear control over mitochondrial citrate synthesis to sustain the increased demand for lipids. Further studies identified mitochondrial deacetylase SIRT3 can reverse ACO2 acetylation, however, SIRT3 expression was found to be significantly lower in prostate tumors. Chromatin analysis revealed that androgen receptor (AR) along with its coregulator SRC-2 recruits HDAC2 on a promoter to repress SIRT3 gene transcription. Analysis of prostate cancer patient datasets identified increased SRC-2 with low levels of SIRT3 were enriched in prostate tumors of patients who are diagnosed with lethal PCa that has spread to other organs such as bones. Using an innovative mouse model that spontaneously develops bone metastasis, we confirmed that the deletion of the SRC-2 gene increased SIRT3 levels, which significantly reduced the growth of prostate tumors in the bone microenvironment.

In summary, our study indicates that blocking the nuclear-mitochondrial communication system facilitated by SRC-2 to enhance ACO2 activity by repressing SIRT3 may have significant clinical benefits to reduce advanced prostate cancer. Our study found a new vulnerability in advanced prostate cancer that could potentially be targeted for clinical benefits.

Written by: Abhisha Sawant Dessai, Aaron Novickis, Subhamoy Dasgupta, Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, New York

References:

  1. Survival Rates for Prostate Cancer. (2020, January 9). Retrieved November 1, 2020, from https://www.cancer.org/cancer/prostate-cancer/detection-diagnosis-staging/survival-rates.html
  2. Zadra, Giorgia, Cornelia Photopoulos, and Massimo Loda. "The fat side of prostate cancer." Biochimica et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipids 1831, no. 10 (2013): 1518-1532.
  3. Dasgupta, Subhamoy, Nagireddy Putluri, Weiwen Long, Bin Zhang, Jianghua Wang, Akash K. Kaushik, James M. Arnold et al. "Coactivator SRC-2–dependent metabolic reprogramming mediates prostate cancer survival and metastasis." The Journal of clinical investigation 125, no. 3 (2015): 1174-1188.
  4. Costello, Leslie C., Yiyan Liu, Renty B. Franklin, and Mary Claire Kennedy. "Zinc inhibition of mitochondrial aconitase and its importance in citrate metabolism of prostate epithelial cells." Journal of Biological Chemistry 272, no. 46 (1997): 28875-28881.
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