title: 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.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania; Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Di Sante
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania; Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Timothy G
authors.initials: TG
authors.lastname: Pestell
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania; Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Mathew C
authors.initials: MC
authors.lastname: Casimiro
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania; Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Sara
authors.initials: S
authors.lastname: Bisetto
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania; Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Powell
authors.affiliation: Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania; Department of Stem Cell Biology and Regenerative Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lisanti
authors.affiliation: Department of Pathology and Urology, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York.
authors.forename: Carlos
authors.initials: C
authors.lastname: Cordon-Cardo
authors.affiliation: Department of Pathology and Urology, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York.
authors.forename: Mireia
authors.initials: M
authors.lastname: Castillo-Martin
authors.affiliation: Department of Pathology and Urology, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York.
authors.forename: Dennis M
authors.initials: DM
authors.lastname: Bonal
authors.affiliation: Department of Pathology, Anatomy, and Cell Biology, MitoCare Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Valentina
authors.initials: V
authors.lastname: Debattisti
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania; Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Ke
authors.initials: K
authors.lastname: Chen
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania; Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Liping
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Medicine and Biochemistry, Ottawa Health Research Institute, University of Ottawa, Ottawa, Ontario, Canada; Department of Microbiology and Immunology, Ottawa Health Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: He
authors.affiliation: Department of Medicine and Biochemistry, Ottawa Health Research Institute, University of Ottawa, Ottawa, Ontario, Canada; Department of Microbiology and Immunology, Ottawa Health Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Michael W
authors.initials: MW
authors.lastname: McBurney
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania; Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. Electronic address: director@kimmelcancercenter.org.
authors.forename: Richard G
authors.initials: RG
authors.lastname: Pestell
mesh_terms: D016475:3T3 Cells; D000818:Animals; D002470:Cell Survival; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000378:metabolism*; D063306:Mitophagy; D018384:Oxidative Stress; D019048:Prostatic Intraepithelial Neoplasia / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D017382:Reactive Oxygen Species / Q000378:metabolism; D056564:Sirtuin 1 / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D000099156:Superoxide Dismutase 2
chemical_list: D006655:Histone Deacetylases; D017382:Reactive Oxygen Species; D056564:Sirtuin 1; D013482:Superoxide Dismutase; D044767:Ubiquitin-Protein Ligases; D000099156:Superoxide Dismutase 2; C111567:parkin protein; C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse