Dataset Information

Sirtuin 6 deficiency induces endothelial cell senescence via downregulation of forkhead box M1 expression.

ABSTRACT: Cellular senescence of endothelial cells causes vascular dysfunction, promotes atherosclerosis, and contributes to the development of age-related vascular diseases. Sirtuin 6 (SIRT6), a conserved NAD+-dependent protein deacetylase, has beneficial effects against aging, despite the fact that its functional mechanisms are largely uncharacterized. Here, we show that SIRT6 protects endothelial cells from senescence. SIRT6 expression is progressively decreased during both oxidative stress-induced senescence and replicative senescence. SIRT6 deficiency leads to endothelial dysfunction, growth arrest, and premature senescence. Using genetically engineered endothelial cell-specific SIRT6 knockout mice, we also show that down-regulation of SIRT6 expression in endothelial cells exacerbates vascular aging. Expression microarray analysis demonstrated that SIRT6 modulates the expression of multiple genes involved in cell cycle regulation. Specifically, SIRT6 appears to regulate the expression of forkhead box M1 (FOXM1), a critical transcription factor for cell cycle progression and senescence. Overexpression of FOXM1 ameliorates SIRT6 deficiency-induced endothelial cell senescence. In this work, we demonstrate the role of SIRT6 as an anti-aging factor in the vasculature. These data may provide the basis for future novel therapeutic approaches against age-related vascular disorders.

SUBMITTER: Lee OH

PROVIDER: S-EPMC7695388 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Sirtuin 6 deficiency induces endothelial cell senescence via downregulation of forkhead box M1 expression.

Lee Ok-Hee OH Woo Yun Mi YM Moon Sohyeon S Lee Jihyun J Park Haeun H Jang Hoon H Park Yun-Yong YY Bae Soo-Kyung SK Park Keun-Hong KH Heo Ji Hoe JH Choi Youngsok Y

Aging 20201110 21

Cellular senescence of endothelial cells causes vascular dysfunction, promotes atherosclerosis, and contributes to the development of age-related vascular diseases. Sirtuin 6 (SIRT6), a conserved NAD+-dependent protein deacetylase, has beneficial effects against aging, despite the fact that its functional mechanisms are largely uncharacterized. Here, we show that SIRT6 protects endothelial cells from senescence. SIRT6 expression is progressively decreased during both oxidative stress-induced sen ...[more]

PMID: 33171439

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Project description:The composition of the prostate microbiome may influence the fate of the cells that may be relevant to prostate morbidity. Several independent studies have reported the presence of the bacterium Propionibacterium acnes in diseased human prostate tissue. It is unclear if the bacterium is an infectious agent, part of a normal prostate microbiota or if it is derived from the skin and accidentally introduced, for instance during a prostate biopsy. Previous research with prostate cell culture and animal models has revealed the capability of P. acnes to establish a low-grade chronic inflammation. However, the fate of primary prostate cells exposed to P. acnes has not been investigated in molecular detail. Here, we investigated the impact of P. acnes on human primary prostate epithelial cells (PrEC). An initial analysis of the host cell response by microarray technology confirmed the inflammation-inducing capability of P. acnes but also showed the deregulation of genes involved in cell cycle, and more specifically in kinetochore and centromere functionality. In particular, we could show and confirm by qPCR that only viable P. acnes downregulated a master regulator of cell cycle progression, FOXM1, as well as its target genes. It was further shown by flow cytometry that P. acnes was indeed able to alter the cell cycle by increasing the number of PrEC cells in S-phase. In search for a molecular explanation we tested the hypothesis that a P.acnes produced berninamycin A-like thiopeptide, that is a structurally closely related to the known FOXM1 inhibitor siomycin A, is responsible for the effect on FOXM1 and the cell cycle. A knock-out mutant in P. acnes was created that lacked the gene encoding the berninamycin A peptide precursor; this mutant was unable to downregulate FOXM1, suggesting that a berninamycin A-like thiopeptide induces cell cycle alterations in PrEC cells. Interestingly, the gene cluster encoding this thiopeptide is restricted to a subtype of P. acnes that is relatively rare on human skin, but more often found in prostate tissue.

Dataset Information

Sirtuin 6 deficiency induces endothelial cell senescence via downregulation of forkhead box M1 expression.

Publications

Sirtuin 6 deficiency induces endothelial cell senescence via downregulation of forkhead box M1 expression.

Similar Datasets

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