Depletion of SIRT6 causes cellular senescence, DNA damage, and telomere dysfunction in human chondrocytes

Nagai, Kazuo; Matsushita, Takehiko; Matsuzaki, Takashi; Takayama, Koji; Matsumoto, Tomoyuki; Kuroda, Ryosuke; Kurosaka, Masahiro

doi:10.1016/j.joca.2015.03.024

Cited by 90 publications

(62 citation statements)

References 47 publications

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“…Consistent with our finding, SIRT6 depletion was reported to induce cellular senescence in several model cell lines. However, most studies on the inhibitory role of SIRT6 in senescence were performed using non-tumorigenic cell lines such as bronchial epithelial cells[30, 31], human fibroblast[32], endothelial cell[33, 34], chondrocyte[35] and keratinocyte[36] in the points of anti-aging effects of SIRT6. In this report, inhibitory roles of SIRT6 in senescence were investigated using tumorigenic cell lines in a normal condition.…”

Section: Discussionmentioning

confidence: 99%

SIRT6 Depletion Suppresses Tumor Growth by Promoting Cellular Senescence Induced by DNA Damage in HCC

Lee

Ryu

Kwon³

et al. 2016

PLoS ONE

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The role of Sirtuin 6 (SIRT6) as a tumor suppressor or oncogene in liver cancer remains controversial. Thus, we identified the specific role of SIRT6 in the progression of hepatocellular carcinoma (HCC). SIRT6 expression was significantly higher in HCC cell lines and HCC tissues from 138 patients than in an immortalized hepatocyte cell line, THLE-2 and non-tumor tissues, respectively. SIRT6 knockdown by shRNA suppressed the growth of HCC cells and inhibited HCC tumor growth in vivo. In addition, SIRT6 silencing significantly prevented the growth of HCC cell lines by inducing cellular senescence in the p16/Rb- and p53/p21-pathway independent manners. Microarray analysis revealed that the expression of genes involved in nucleosome assembly was apparently altered in SIRT6-depleted Hep3B cells. SIRT6 knockdown promoted G2/M phase arrest and downregulation of genes encoding histone variants associated with nucleosome assembly, which could be attributed to DNA damage. Taken together, our findings suggest that SIRT6 acts as a tumor promoter by preventing DNA damage and cellular senescence, indicating that SIRT6 represents a potential therapeutic target for the treatment of HCC.

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Section: Discussionmentioning

confidence: 99%

SIRT6 Depletion Suppresses Tumor Growth by Promoting Cellular Senescence Induced by DNA Damage in HCC

Lee

Ryu

Kwon³

et al. 2016

PLoS ONE

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“…In addition, silencing of SIRT6 in HUVEC activates the p21 pathway [37], whereas overexpression of SIRT6 inhibits TGF-β-induced senescence of epithelial cells via proteasomal degradation of p21 [38]. However, SIRT6 inhibition in chondrocytes leads to p21 downregulation due to the time of the extraction of protein [42], as p21 is up-regulated during the early stage of senescence and decreases once senescence was achieved [43]. Depletion of SIRT6 leads to p16 upregulation in chondrocytes [42] and bone marrow mesenchymal stem cell (BM-MSC) [44].…”

Section: Discussionmentioning

confidence: 99%

“…However, SIRT6 inhibition in chondrocytes leads to p21 downregulation due to the time of the extraction of protein [42], as p21 is up-regulated during the early stage of senescence and decreases once senescence was achieved [43]. Depletion of SIRT6 leads to p16 upregulation in chondrocytes [42] and bone marrow mesenchymal stem cell (BM-MSC) [44]. Overexpression of SIRT6 decreases p16 protein levels in chondrocytes [45].…”

Section: Discussionmentioning

confidence: 99%

SIRT6 delays cellular senescence by promoting p27Kip1 ubiquitin-proteasome degradation

Zhao

Wang

et al. 2016

Aging

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Sirtuin6 (SIRT6) has been implicated as a key factor in aging and aging-related diseases. However, the role of SIRT6 in cellular senescence has not been fully understood. Here, we show that SIRT6 repressed the expression of p27Kip1 (p27) in cellular senescence. The expression of SIRT6 was reduced during cellular senescence, whereas enforced SIRT6 expression promoted cell proliferation and antagonized cellular senescence. In addition, we demonstrated that SIRT6 promoted p27 degradation by proteasome and SIRT6 decreased the acetylation level and protein half-life of p27. p27 acetylation increased its protein stability. Furthermore, SIRT6 directly interacted with p27. Importantly, p27 was strongly acetylated and had a prolonged protein half-life with the reduction of SIRT6 when cells were senescent, compared with those young cells. Finally, SIRT6 markedly rescued senescence induced by p27. Our findings indicate that SIRT6 decreases p27 acetylation, leading to its degradation via ubiquitin-proteasome pathway and then delays cellular senescence.

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“…As such, there is a paucity of research on how other sirtuins regulate chondrocyte function. However, depletion of SIRT6 in human chondrocytes (achieved using RNA interference) resulted in substantially increased DNA damage and telomere dysfunction, which was associated with premature senescence 98 . SIRT6 depletion also increased expression of MMP1 and MMP13 , which are implicated in the pathogenesis of OA.…”

Section: Dysfunctional Energy Metabolismmentioning

confidence: 99%

Ageing and the pathogenesis of osteoarthritis

Loeser¹,

Collins²,

2016

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Ageing-associated changes that affect articular tissues promote the development of osteoarthritis (OA). Although ageing and OA are closely linked, they are independent processes. Several potential mechanisms by which ageing contributes to OA have been elucidated. This Review focuses on the contributions of the following factors: age-related inflammation (also referred to as ‘inflammaging’); cellular senescence (including the senescence-associated secretory phenotype (SASP)); mitochondrial dysfunction and oxidative stress; dysfunction in energy metabolism due to reduced activity of 5′-AMP-activated protein kinase (AMPK), which is associated with reduced autophagy; and alterations in cell signalling due to age-related changes in the extracellular matrix. These various processes contribute to the development of OA by promoting a proinflammatory, catabolic state accompanied by increased susceptibility to cell death that together lead to increased joint tissue destruction and defective repair of damaged matrix. The majority of studies to date have focused on articular cartilage, and it will be important to determine whether similar mechanisms occur in other joint tissues. Improved understanding of ageing-related mechanisms that promote OA could lead to the discovery of new targets for therapies that aim to slow or stop the progression of this chronic and disabling condition.

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Depletion of SIRT6 causes cellular senescence, DNA damage, and telomere dysfunction in human chondrocytes

Abstract: Depletion of SIRT6 in human chondrocytes caused increased DNA damage and telomere dysfunction, and subsequent premature senescence. These findings suggest that SIRT6 plays an important role in the regulation of senescence of human chondrocytes.

Cited by 90 publications

References 47 publications

SIRT6 Depletion Suppresses Tumor Growth by Promoting Cellular Senescence Induced by DNA Damage in HCC

SIRT6 Depletion Suppresses Tumor Growth by Promoting Cellular Senescence Induced by DNA Damage in HCC

SIRT6 delays cellular senescence by promoting p27Kip1 ubiquitin-proteasome degradation

Ageing and the pathogenesis of osteoarthritis

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