Sirtuins in Metabolic and Epigenetic Regulation of Stem Cells

Fang, Yi; Táng, Shuāng; Li, Xiaoling

doi:10.1016/j.tem.2018.12.002

Cited by 51 publications

(37 citation statements)

References 90 publications

(112 reference statements)

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“…Mechanistically, these classes are zinc-dependent and referred to as 'classical HDACs' [6,7]. In contrast, class III HDACs (sirtuins 1-7) are NAD + -dependent [8]. The biological role of HDACs is to generate and maintain the balance between protein (histone) acetylation and deacetylation.…”

Section: Introductionmentioning

confidence: 99%

HDAC Screening Identifies the HDAC Class I Inhibitor Romidepsin as a Promising Epigenetic Drug for Biliary Tract Cancer

Mayr

Kiesslich

Erber

et al. 2021

Cancers

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Inhibition of histone deacetylases (HDACs) is a promising anti-cancer approach. For biliary tract cancer (BTC), only limited therapeutic options are currently available. Therefore, we performed a comprehensive investigation of HDAC expression and pharmacological HDAC inhibition into a panel of eight established BTC cell lines. The screening results indicate a heterogeneous expression of HDACs across the studied cell lines. We next tested the effect of six established HDAC inhibitors (HDACi) covering pan- and class-specific HDACis on cell viability of BTC cells and found that the effect (i) is dose- and cell-line-dependent, (ii) does not correlate with HDAC isoform expression, and (iii) is most pronounced for romidepsin (a class I HDACi), showing the highest reduction in cell viability with IC50 values in the low-nM range. Further analyses demonstrated that romidepsin induces apoptosis in BTC cells, reduces HDAC activity, and increases acetylation of histone 3 lysine 9 (H3K9Ac). Similar to BTC cell lines, HDAC 1/2 proteins were heterogeneously expressed in a cohort of resected BTC specimens (n = 78), and their expression increased with tumor grading. The survival of BTC patients with high HDAC-2-expressing tumors was significantly shorter. In conclusion, HDAC class I inhibition in BTC cells by romidepsin is highly effective in vitro and encourages further in vivo evaluation in BTC. In situ assessment of HDAC 2 expression in BTC specimens indicates its importance for oncogenesis and/or progression of BTC as well as for the prognosis of BTC patients.

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Section: Introductionmentioning

confidence: 99%

HDAC Screening Identifies the HDAC Class I Inhibitor Romidepsin as a Promising Epigenetic Drug for Biliary Tract Cancer

Mayr

Kiesslich

Erber

et al. 2021

Cancers

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“…16 Sirtuin proteins are involved in regulation of metabolism, proliferation, differentiation and cell survival. 17 SIRT1 protein prevents intestinal inflammation by regulating the gut microbiota. 18 SIRT1 deficiency in the intestine specifically activates secretory cells, as is evident by the elevated number of intestinal Paneth and goblet cells without alteration of other cell types or the proliferation rate of IECs.…”

mentioning

confidence: 99%

SIRT2 Contributes to the Regulation of Intestinal Cell Proliferation and Differentiation

Zhou

Rychahou

et al. 2020

Cellular and Molecular Gastroenterology and Hepatology

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Using complementary approaches (intestinal epithelial cell lines, intestinal organoids and SIRT2 knockout mice), we demonstrated that SIRT2, decreased in intestinal tissues from patients with inflammatory bowel diseases, contributes to the maintenance of intestinal epithelium homeostasis through regulation of Wnt-b-catenin signaling. BACKGROUND AND AIMS: Intestinal mucosa undergoes a continual process of proliferation, differentiation, and apoptosis. Disruption of this homeostasis is associated with disorders such as inflammatory bowel disease (IBD). We investigated the role of Sirtuin 2 (SIRT2), a NAD-dependent protein deacetylase, in intestinal epithelial cell (IEC) proliferation and differentiation and the mechanism by which SIRT2 contributes to maintenance of intestinal cell homeostasis. METHODS: IECs were collected from SIRT2-deficient mice and patients with IBD. Expression of SIRT2, differentiation markers (mucin2, intestinal alkaline phosphatase, villin, Na,K-ATPase, and lysozyme) and Wnt target genes (EPHB2, AXIN2, and cyclin D1) was determined by western blot, real-time RT-PCR, or immunohistochemical (IHC) staining. IECs were treated with TNF or transfected with siRNA targeting SIRT2. Proliferation was determined by villus height and crypt depth, and Ki67 and cyclin D1 IHC staining. For studies using organoids, intestinal crypts were isolated. RESULTS: Increased SIRT2 expression was localized to the more differentiated region of the intestine. In contrast, SIRT2 deficiency impaired proliferation and differentiation and altered stemness in the small intestinal epithelium ex vivo and in vivo. SIRT2-deficient mice showed decreased intestinal enterocyte and goblet cell differentiation but increased the Paneth cell lineage and increased proliferation of IECs. Moreover, we found that SIRT2 inhibits Wnt/b-catenin signaling, which critically regulates IEC proliferation and differentiation. Consistent with a distinct role for SIRT2 in maintenance of gut homeostasis, intestinal mucosa from IBD patients exhibited decreased SIRT2 expression. CONCLUSION: We demonstrate that SIRT2, which is decreased in intestinal tissues from IBD patients, regulates Wnt-b-catenin signaling and is important for maintenance of IEC proliferation and differentiation.

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“…This mechanism, which links metabolic and stress changes with epigenetic modifications of the DNA, is of special relevance to maintaining genomic integrity (Bosch-Presegue and Vaquero, 2015). This mechanism has been suggested to be fundamental for regulating epigenetic processes in stem cells (Fang et al, 2019). Ryall et al (2015) showed in vitro by using cultured mouse SCs and in vivo by using SIRT1 deacetylase domain ablation mouse models that the shift from fatty acid oxidation to glycolytic metabolism in activated SCs produces less intracellular NAD+ and consequently less SIRT1 activity, which ultimately leads to histone acetylation and the activation of muscle-specific gene transcription that promotes myogenesis ( Figure 1B).…”

Section: Metabolic Regulation Of Satellite Cells During Regenerationmentioning

confidence: 93%

Lactate Metabolism and Satellite Cell Fate

2020

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Lactate is one of the metabolic products of glycolysis. It is widely accepted as an important energy source for many cell types and more recently has been proposed to actively participate in cell-cell communication. Satellite cells (SCs), which are adult skeletal muscle stem cells, are the main players of the skeletal muscle regeneration process. Recent studies have proposed a metabolic switch to increase glycolysis in activated SCs. Moreover, lactate has been shown to affect SCs and myoblasts in vivo and in vitro. In this short review, we describe how metabolic variations relate with SC fate (quiescence, activation, proliferation, migration, differentiation, fusion, and self-renewal), as well as discuss possible relationships between lactate as a metabolite and as a signaling molecule affecting SC fate.

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Sirtuins in Metabolic and Epigenetic Regulation of Stem Cells

Cited by 51 publications

References 90 publications

HDAC Screening Identifies the HDAC Class I Inhibitor Romidepsin as a Promising Epigenetic Drug for Biliary Tract Cancer

HDAC Screening Identifies the HDAC Class I Inhibitor Romidepsin as a Promising Epigenetic Drug for Biliary Tract Cancer

SIRT2 Contributes to the Regulation of Intestinal Cell Proliferation and Differentiation

Lactate Metabolism and Satellite Cell Fate

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