Loss of Sirt1 Promotes Prostatic Intraepithelial Neoplasia, Reduces Mitophagy, and Delays Park2 Translocation to Mitochondria
Male
Prostatic Intraepithelial Neoplasia
Genotype
Cell Survival
Mitophagy
Prostatic Neoplasms
Mice, Transgenic
3T3 Cells
Immunohistochemistry
Histone Deacetylases
Pathology and Forensic Medicine
Mitochondria
Gene Expression Regulation, Neoplastic
Mice
Oxidative Stress
Protein Transport
Microscopy, Fluorescence
Sirtuin 1
Animals
Humans
Reactive Oxygen Species
DOI:
10.1016/j.ajpath.2014.09.014
Publication Date:
2014-12-18T05:47:59Z
AUTHORS (15)
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.
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