New insight in molecular mechanisms regulating SIRT6 expression in diabetes: Hyperglycaemia effects on <i>SIRT6</i> DNA methylation

Rizzo, Maria Rosaria; Marfella, Raffaele; Cataldo, Vittoria; Fontanella, Rosaria Anna; Boccalone, Eugenio; Paolisso, Giuseppe; Barbieri, Michelangela

doi:10.1002/jcp.30185

Cited by 12 publications

(10 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…4C ). Numerous studies have pointed to promoter hypermethylation as a mechanism for SIRT6 gene repression [ 24 – 26 ]. Indeed, bisulfite assay demonstrated that oxLDL treatment stimulated SIRT6 promoter hypermethylation, however, NAC treatment neutralized the effect of oxLDL on SIRT6 promoter methylation (Fig.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

SIRT6 mediates MRTF-A deacetylation in vascular endothelial cells to antagonize oxLDL-induced ICAM-1 transcription

et al. 2022

View full text Add to dashboard Cite

Oxidized low-density lipoprotein (oxLDL), a known risk factor for atherosclerosis, activates the transcription of adhesion molecules (ICAM-1) in endothelial cells. We previously showed that myocardin-related transcription factor A (MRTF-A) mediates oxLDL-induced ICAM-1 transcription. Here we confirm that ICAM-1 transactivation paralleled dynamic alterations in MRTF-A acetylation. Since treatment with the antioxidant NAC dampened MRTF-A acetylation, MRTF-A acetylation appeared to be sensitive to cellular redox status. Of interest, silencing of SIRT6, a lysine deacetylase, restored MRTF-A acetylation despite the addition of NAC. SIRT6 directly interacted with MRTF-A to modulate MRTF-A acetylation. Deacetylation of MRTF-A by SIRT6 led to its nuclear expulsion thus dampening MRTF-A occupancy on the ICAM-1 promoter. Moreover, SIRT6 expression was downregulated with oxLDL stimulation likely owing to promoter hypermethylation in endothelial cells. DNA methyltransferase 1 (DNMT1) was recruited to the SIRT6 promoter and mediated SIRT6 repression. The ability of DNMT1 to repress SIRT6 promoter partly was dependent on ROS-sensitive serine 154 phosphorylation. In conclusion, our data unveil a novel DNMT1-SIRT6 axis that contributes to the regulation of MRTF-A acetylation and ICAM-1 transactivation in endothelial cells.

show abstract

Section: Resultsmentioning

confidence: 99%

“…SIRT6 promoter methylation status was analyzed with bisulfite conversion followed by sequencing essentially as described previously [ 24 , 25 ]. Briefly, genomic DNA isolated from EAhy926 cells was subjected to bisulfite treatment using the EZ DNA Methylation Gold Kit (ZymoResearch).…”

Section: Methodsmentioning

confidence: 99%

SIRT6 mediates MRTF-A deacetylation in vascular endothelial cells to antagonize oxLDL-induced ICAM-1 transcription

et al. 2022

View full text Add to dashboard Cite

show abstract

“…In contrast, both high glucose levels in vitro and maternal diabetes in vivo significantly reduced the SIRT6 level in the embryo or neural stem cells [ 43 ]. Interestingly, a separate study demonstrated that high glucose exposure was associated with increased demethylation of the SIRT6 promoter and increased SIRT6 mRNA transcription [ 44 ]. Translation or posttranslational modifications might be feasible explanations for the discrepancy observed in the regulatory mechanisms of SIRT6.…”

Section: The Molecular Network That Regulates Sirt6mentioning

confidence: 99%

SIRT6 in Aging, Metabolism, Inflammation and Cardiovascular Diseases

Guo¹,

Ge²,

Li³

2022

Aging and disease

View full text Add to dashboard Cite

As an important NAD + -dependent enzyme, SIRT6 has received significant attention since its discovery. In view of observations that SIRT6-deficient animals exhibit genomic instability and metabolic disorders and undergo early death, SIRT6 has long been considered a protein of longevity. Recently, growing evidence has demonstrated that SIRT6 functions as a deacetylase, mono-ADP-ribosyltransferase and long fatty deacylase and participates in a variety of cellular signaling pathways from DNA damage repair in the early stage to disease progression. In this review, we elaborate on the specific substrates and molecular mechanisms of SIRT6 in various physiological and pathological processes in detail, emphasizing its links to aging (genomic damage, telomere integrity, DNA repair), metabolism (glycolysis, gluconeogenesis, insulin secretion and lipid synthesis, lipolysis, thermogenesis), inflammation and cardiovascular diseases (atherosclerosis, cardiac hypertrophy, heart failure, ischemia-reperfusion injury). In addition, the most recent advances regarding SIRT6 modulators (agonists and inhibitors) as potential therapeutic agents for SIRT6-mediated diseases are reviewed.

show abstract

“…The downregulated SIRT1 expression is correlated with pro-inflammatory cytokines production and reduced myocardial function [ 33 ]. Diabetic hyperglycemia occurs via methylation on SIRT6 promoter, thus determining SIRT6 downregulation in TeloHAEC cells exposed to high glucose concentrations [ 34 ]. In vitro exposure to high glucose concentrations also determined downregulation of SIRT6 in podocytes, causing mitochondrial alteration, increased ROS production and phosphorylation of AMP-activated protein kinase (p-AMPK) [ 35 ].…”

Section: Sirtuins As Modulators Of Chronic Degenerative Diseasesmentioning

confidence: 99%

Mitochondrial Sirtuins in Chronic Degenerative Diseases: New Metabolic Targets in Colorectal Cancer

Colloca¹,

Balestrieri²,

Anastasio³

et al. 2022

IJMS

View full text Add to dashboard Cite

Sirtuins (SIRTs) are a family of class III histone deacetylases (HDACs) consisting of seven members, widely expressed in mammals. SIRTs mainly participate in metabolic homeostasis, DNA damage repair, cell survival, and differentiation, as well as other cancer-related biological processes. Growing evidence shows that SIRTs have pivotal roles in chronic degenerative diseases, including colorectal cancer (CRC), the third most frequent malignant disease worldwide. Metabolic alterations are gaining attention in the context of CRC development and progression, with mitochondrion representing a crucial point of complex and intricate molecular mechanisms. Mitochondrial SIRTs, SIRT2, SIRT3, SIRT4 and SIRT5, control mitochondrial homeostasis and dynamics. Here, we provide a comprehensive review on the latest advances on the role of mitochondrial SIRTs in the initiation, promotion and progression of CRC. A deeper understanding of the pathways by which mitochondrial SIRTs control CRC metabolism may provide new molecular targets for future innovative strategies for CRC prevention and therapy.

show abstract

New insight in molecular mechanisms regulating SIRT6 expression in diabetes: Hyperglycaemia effects on SIRT6 DNA methylation

Cited by 12 publications

References 31 publications

SIRT6 mediates MRTF-A deacetylation in vascular endothelial cells to antagonize oxLDL-induced ICAM-1 transcription

SIRT6 mediates MRTF-A deacetylation in vascular endothelial cells to antagonize oxLDL-induced ICAM-1 transcription

SIRT6 in Aging, Metabolism, Inflammation and Cardiovascular Diseases

Mitochondrial Sirtuins in Chronic Degenerative Diseases: New Metabolic Targets in Colorectal Cancer

Contact Info

Product

Resources

About