Loss of Sirt1 Promotes Prostatic Intraepithelial Neoplasia, Reduces Mitophagy, and Delays Park2 Translocation to Mitochondria

• DOI: 10.1016/j.ajpath.2014.09.014
• Publication Date: 2014-12-18T05:47:59Z
• Authors: Gabriele Di Sante; Timothy G. Pestell; Mathew C. Casimiro; Sara Bisetto; Michael J. Powell; Michael P. Lisanti; Carlos Cordon-Cardo; Mireia Castillo-M...; Dennis M. Bonal; Valentina Debattisti; Ke Chen; Liping Wang; Xiaohong He; Michael W. McBurney; Richard G. Pestell
• Keywords: SOD2; Sirtuin 1

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