Sirtuins, nuclear hormone receptor acetylation and transcriptional regulation

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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“…1,2 The SIRT1 human homologue of the yeast Saccharomyces cerevisiae, the Sir2 gene, regulates co-activators (p300/calcium-binding protein), 3 …”

mentioning

confidence: 99%

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

Sante

Pestell

Casimiro

et al. 2015

The American Journal of Pathology

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“…However, even without nutritional deficiency of methyl groups, impaired synthesis of SAM and perturbed DNA methylation can happen when the need for the synthesis of the detoxification enzyme glutathione transferase (GST) synthesis increases [184]. Diets or nutritional compounds that affect energy metabolism or mitochondrial respiration can have global epigenetic effects on changes in NAD + availability and SIRT activity [185]. Since SIRT activation has been linked to longevity (increased lifespan and healthy aging) and mimics a calorie-restricted diet, SIRT activators such as resveratrol represent a major class of caloric restriction mimetic phytochemicals that could reverse metabolic disease [182].…”

Section: Nutriepigenomics: Lifelong Remodeling Of Our Epigenomes By Nmentioning

confidence: 99%

Connecting Phytochemicals, Epigenetics, and Healthy Aging

Szic

Palagani

Chirumamilla

et al. 2014

Inflammation, Advancing Age and Nutrition

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“…Furthermore, even without nutritional deficiency of methyl groups, impaired synthesis of SAM and perturbed DNA methylation can happen when the need for the synthesis of the detoxification enzyme glutathione transferase (GSH) synthesis increases (D. H. ). Diets or nutritional compounds which affect energy metabolism or mitochondrial respiration can have global epigenetic effects upon changes in NAD+ availability and SIRT activity (Whittle et al, 2007). Since SIRT activation has been linked to longevity (increased lifespan and healthy aging) and mimics a caloric restricted diet, SIRT activators such as resveratrol represent a major class of caloric mimetic epigenetic modulator phytochemicals which could reverse metabolic disease (Imai & Guarente, 2010).…”

Section: Epigenetic Targets Of Bioactive Dietary Components For Cancementioning

confidence: 99%