Loss of Sirt1 promotes prostatic intraepithelial neoplasia, reduces mitophagy, and delays PARK2 translocation to mitochondria.

Abstract

Prostatic intraepithelial neoplasia is a precursor to prostate cancer. Herein, deletion of the NAD(+)-dependent histone deacetylase Sirt1 induced histological features of prostatic intraepithelial neoplasia at 7 months of age; these features were associated with increased cell proliferation and enhanced mitophagy. In human prostate cancer, lower Sirt1 expression in the luminal epithelium was associated with poor prognosis. Genetic deletion of Sirt1 increased mitochondrial superoxide dismutase 2 (Sod2) acetylation of lysine residue 68, thereby enhancing reactive oxygen species (ROS) production and reducing SOD2 activity. The PARK2 gene, which has several features of a tumor suppressor, encodes an E3 ubiquitin ligase that participates in removal of damaged mitochondria via mitophagy. Increased ROS in Sirt1(-/-) cells enhanced the recruitment of Park2 to the mitochondria, inducing mitophagy. Sirt1 restoration inhibited PARK2 translocation and ROS production requiring the Sirt1 catalytic domain. Thus, the NAD(+)-dependent inhibition of SOD2 activity and ROS by SIRT1 provides a gatekeeper function to reduce PARK2-mediated mitophagy and aberrant cell survival.

• Authors: Gabriele Di Sante, Timothy G Pestell, Mathew C Casimiro, Sara Bisetto, Michael J Powell, Michael P Lisanti, Carlos Cordon-Cardo, Mireia Castillo-Martin, Dennis M Bonal, Valentina Debattisti, Ke Chen, Liping Wang, Xiaohong He, Michael W McBurney, Richard G Pestell
• Journal: The American journal of pathology (Am J Pathol) Vol. 185 Issue 1 Pg. 266-79 (Jan 2015) ISSN: 1525-2191 [Electronic] United States
• PMID: 25529796 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Reactive Oxygen Species
• Superoxide Dismutase
• superoxide dismutase 2
• Ubiquitin-Protein Ligases
• parkin protein
• SIRT1 protein, human
• Sirt1 protein, mouse
• Sirtuin 1
• Histone Deacetylases

Topics

• 3T3 Cells
• Animals
• Cell Survival
• Gene Expression Regulation, Neoplastic
• Genotype
• Histone Deacetylases (metabolism)
• Humans
• Immunohistochemistry
• Male
• Mice
• Mice, Transgenic
• Microscopy, Fluorescence
• Mitochondria (metabolism)
• Mitophagy
• Oxidative Stress
• Prostatic Intraepithelial Neoplasia (metabolism)
• Prostatic Neoplasms (genetics, metabolism)
• Protein Transport
• Reactive Oxygen Species (metabolism)
• Sirtuin 1 (metabolism)
• Superoxide Dismutase (metabolism)
• Ubiquitin-Protein Ligases (metabolism)