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Jiangying Kuang, Lei Chen, Qin Tang, Jinhang Zhang, Yanping Li, Jinhan He
Sirt6 is one of the sirtuin family members, a kind of NAD+-dependent histone deacetylase and ADP-ribose transferase enzyme. It has an important role in physiological and pathological processes, regulating aging, cancer, obesity, insulin resistance, inflammation, and energy metabolism. Recent studies have suggested that reduced Sirt6 action is related to obesity and diabetes. Aging and overnutrition, two major risk factors for obesity and diabetes, lead to decreased Sirt6 level and function, which results in abnormal glucose and lipid metabolism...
2018: Frontiers in Physiology
Jinghua Liu, Zhen Yu, Yuanyuan Xiao, Qiong Meng, Yeying Wang, Wei Chang
Background: The Forkhead transcription family member FOXA2 plays a fundamental role in hepatocellular carcinoma (HCC) progression, but the precise interaction factor and molecular regulation of FOXA2 are not fully understood. Objective: In this study, we found that FOXA2 could interact with sirtuin 6 (SIRT6) directly in vivo and in vitro. We explored that the expressions of FOXA2 and SIRT6 were significantly downregulated in human HCC and HCC cell lines. Methods: Functionally, cell counting kit-8 assay and Transwell® assay were performed; we demonstrated that the knockdown of FOXA2 and SIRT6 promoted HepG2 cells and Huh7 cells proliferation and invasion in vitro...
2018: Cancer Management and Research
Minna Rahnasto-Rilla, Jonna Tyni, Marjo Huovinen, Elina Jarho, Tomasz Kulikowicz, Sarangan Ravichandran, Vilhelm A Bohr, Luigi Ferrucci, Maija Lahtela-Kakkonen, Ruin Moaddel
Flavonoids are polyphenolic secondary metabolites synthesized by plants and fungus with various pharmacological effects. Due to their plethora of biological activities, they have been studied extensively in drug development. They have been shown to modulate the activity of a NAD+ -dependent histone deacetylase, SIRT6. Because SIRT6 has been implicated in longevity, metabolism, DNA-repair, and inflammatory response reduction, it is an interesting target in inflammatory and metabolic diseases as well as in cancer...
March 7, 2018: Scientific Reports
Xing-Xing He, Chen-Kai Huang, Bu-Shan Xie
The exact molecular mechanism of 5-fluorouracil (5-FU) in human gastric cancer cells remains to be elucidated. Cultured BGC‑823 human gastric carcinoma and AGS cell lines were treated with 5‑FU. Autophagosome formation was investigated through multiple approaches, including the quantification of green fluorescent protein‑microtubule‑associated protein 1A/1B‑light chain 3 (LC3) puncta, LC3 conversion and electron microscopy observations. Additionally, autophagy was inhibited using 3‑methyladenine (3‑MA) and beclin‑1 ablation, to determine its role in 5‑FU‑mediated cell death...
March 1, 2018: Molecular Medicine Reports
Ning Li, Dong Mao, Yansha Cao, Hua Li, Fu Ren, Keyan Li
Sirtuin 6 (SIRT6) is a member of the nicotinamide adenine dinucleotide positivity-dependent class III deacetylase sirtuin family. The present study aimed to explore the expression and function of SIRT6 in colon cancer. Furthermore, the partial mechanism underlying the dysregulation of SIRT6 was investigated. The results of immunohistochemistry demonstrated that SIRT6 was markedly downregulated in colon cancer tissues, and patients with high SIRT6 expression had a better prognosis than those who did not. The proliferation and apoptotic assays demonstrated that SIRT6 was able to suppress colon cancer cell proliferation and induce apoptosis via the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway...
March 5, 2018: International Journal of Oncology
Or Gertman, Dotan Omer, Adi Hendler, Daniel Stein, Lior Onn, Yana Khukhin, Miguel Portillo, Raz Zarivach, Haim Y Cohen, Debra Toiber, Amir Aharoni
Mammalian SIRT6 is a well-studied histone deacetylase that was recently shown to exhibit high protein deacylation activity enabling the removal of long chain fatty acyl groups from proteins. SIRT6 was shown to play key roles in cellular homeostasis by regulating a variety of cellular processes including DNA repair and glucose metabolism. However, the link between SIRT6 enzymatic activities and its cellular functions is not clear. Here, we utilized a directed enzyme evolution approach to generate SIRT6 mutants with improved deacylation activity...
February 23, 2018: Scientific Reports
Shrestha Ghosh, Sheung Kin Wong, Zhixin Jiang, Baohua Liu, Yi Wang, Quan Hao, Vera Gorbunova, Xinguang Liu, Zhongjun Zhou
Mammalian sirtuin 6 (Sirt6) is a conserved NAD+ -dependent deacylase and mono-ADP ribosylase that is known to be involved in DNA damage repair, metabolic homeostasis, inflammation, tumorigenesis, and aging. Loss of Sirt6 in mice results in accelerated aging and premature death within a month. Here, we show that haploinsufficiency ( i.e. , heterozygous deletion) of Trp53 dramatically extends the lifespan of both female and male Sirt6 -deficient mice. Haploinsufficiency of Trp53 in Sirt6 -deficient mice rescues several age-related phenotypes of Sirt6-deficient mice, including reduced body size and weight, lordokyphosis, colitis, premature senescence, apoptosis, and bone marrow stem cell decline...
February 23, 2018: ELife
Latifa Al-Haj, Khalid S A Khabar
The enzyme pyrimidine 5'-nucleotidase (NT5C3A), which mediates nucleotide catabolism, was previously thought to be restricted to blood cells. We showed that expression of the gene encoding NT5C3A was induced by type I interferons (IFNs) in multiple cell types and that NT5C3A suppressed cytokine production through inhibition of the nuclear factor κB (NF-κB) pathway. NT5C3A expression required both an intronic IFN-stimulated response element and the IFN-stimulated transcription factor IRF1. Overexpression of NT5C3A, but not of its catalytic mutants, suppressed IL-8 production by HEK293 cells...
February 20, 2018: Science Signaling
Carla Tatone, Giovanna Di Emidio, Arcangelo Barbonetti, Gaspare Carta, Alberto M Luciano, Stefano Falone, Fernanda Amicarelli
BACKGROUND: Sirtuins (SIRT1-7) are a family of NAD+-dependent deacetylases that catalyze post-translational modifications of proteins. Together, they respond to metabolic challenges, inflammatory signals or hypoxic/oxidative stress, and are associated with aging and longevity. The role of Sirtuins in the regulation of fertility emerged in 2003 when a defective reproductive phenotype was observed in SIRT1-null mice. Although studies on Sirtuins in reproductive biology have been increasing in the last years, a recent comprehensive update on this issue is still lacking...
February 13, 2018: Human Reproduction Update
Kana Tanabe, Jiaan Liu, Daiki Kato, Hitoshi Kurumizaka, Kenzo Yamatsugu, Motomu Kanai, Shigehiro A Kawashima
Chromatin structure and gene expression are dynamically regulated by posttranslational modifications of histones. Recent advance in mass spectrometry has identified novel types of lysine acylations, such as butyrylation and malonylation, whose functions and regulations are likely different from those of acetylation. Sirtuins, nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylases, catalyze various deacylations. However, it is poorly understood how distinct sirtuins regulate the histone acylation states of nucleosomes that have many lysine residues...
February 8, 2018: Scientific Reports
Touseef Sheikh, Piyushi Gupta, Pruthvi Gowda, Shruti Patrick, Ellora Sen
A dynamic network of metabolic adaptations, inflammatory responses and redox homeostasis is known to drive tumor progression. A considerable overlap between these processes exists, but several of their key regulators remain unknown. To this end, here we investigated the role of the proinflammatory cytokine IL-1β in connecting these processes in glioma cells. We found that glucose starvation sensitizes glioma cells to IL-1β-induced apoptosis in a manner that depended on reactive oxygen species (ROS). Although IL-1β-induced JNK had no effect on cell viability under glucose deprivation, it mediated nuclear translocation of hexokinase 2 (HK2)...
February 6, 2018: Journal of Biological Chemistry
Yiji Feng, Jian Liang, Yuanqi Zhai, Junran Sun, Jing Wang, Xiangjun She, Qing Gu, Yang Liu, Hong Zhu, Xueting Luo, Xiaodong Sun
Age-associated dysfunction of retinal pigment epithelial cells (RPEs) is considered to be the initial trigger of retinal diseases such as age-related macular degeneration. Although autophagy is upregulated in RPEs during the course of aging, little is known about how autophagy is regulated and its functional role in RPEs. In this study, we found that expression of Sirtuin 6 (SIRT6) and autophagic markers are upregulated in RPEs of aged mice where subretinal deposition of amyloid-β is accumulated and in amyloid-β stimulated RPEs...
February 19, 2018: Biochemical and Biophysical Research Communications
Fangyi Liu, Heng-Fu Bu, Hua Geng, Isabelle G De Plaen, Chao Gao, Peng Wang, Xiao Wang, Jacob A Kurowski, Hong Yang, Jiaming Qian, Xiao-Di Tan
Sirtuin-6 (Sirt6) is a critical epigenetic regulator, but its function in the gut is unknown. Here, we studied the role of intestinal epithelial Sirt6 in colitis-associated intestinal epithelial injury. We found that Sirt6, which is predominantly expressed in epithelial cells in intestinal crypts, is decreased in colitis in both mice and humans. Colitis-derived inflammatory mediators including interferon-γ and reactive oxygen species strongly inhibited Sirt6 protein expression in young adult mouse colonocyte (YAMC) cells...
October 23, 2017: Molecular Medicine
Ha Yong Song, Eric J Rellinger, Seong-Hoon Park, Pritha Paul, Jingbo Qiao, Athanasios Vasilopoulos, Ozkan Ozden, David Gius, Dai H Chung
BACKGROUND/AIM: Sirtuins (SIRTs) play crucial roles in various signaling pathways that modulate differentiation and proliferation. We sought to elucidate the role of SIRTs in differentiation and proliferation of human neuroblastoma (NB). MATERIALS AND METHODS: NB cells were treated with nicotinamide (NAM), a non-specific SIRT inhibitor, SIRT-targeted short hairpin RNAs, and retinoic acid to assess cell growth and differentiation. RESULTS: SIRTs are involved in proliferation and differentiation using NAM in BE(2)-C cells...
February 2018: Anticancer Research
Zhongchi Li, Kang Xu, Nannan Zhang, Gabriel Amador, Yanying Wang, Sen Zhao, Liyuan Li, Ying Qiu, Zhao Wang
Sirtuin 6 (SIRT6) is a NAD+-dependent deacetylase associated with numerous aspects of health and physiology. Overexpression of SIRT6 has emerged as a protector in cardiac tissues against pathologic cardiac hypertrophy. However, the mechanism of this protective effect is not fully understood. Here, both in vivo and in vitro results demonstrated that SIRT6 overexpression can attenuate cisplatin-induced kidney injury in terms of renal dysfunction, inflammation and apoptosis. In addition, SIRT6 knockout aggravated kidney injury caused by cisplatin...
January 16, 2018: Kidney International
Tong Jing, Kuang Ya-Shu, Wang Xue-Jun, Hou Han-Jing, Lai Yan, Yao Yi-An, Chen Fei, Liu Xue-Bo
Background: Endothelial microparticles (EMPs) are small vesicles released by endothelial cells (ECs); they are considered biomarkers for endothelial dysfunction and therapeutic targets in diabetes-related vascular disease. Sirtuins have also been shown to play important roles in diabetes by regulating endothelial dysfunction. However, the effect of sirtuin-incorporated EMPs on their parental ECs remains unknown. Aim: The present study aims to investigate the diagnostic value of EMPs in diabetes and detect the protective effects of sirtuin 6 (Sirt6) mRNA -incorporated EMPs on endothelial dysfunction...
December 26, 2017: Oncotarget
Bojin Zhu, Yongjin Yan, Boyun Shao, Luwen Tian, Weihua Zhou
Objective To explore the prognostic significance of nicotinamide adenine dinucleotide (NAD)-dependent protein deacetylase sirtuin-6 (SIRT6), encoded by the sirtuin 6 ( SIRT6) gene, in a population of Chinese Han patients with non-small cell lung cancer (NSCLC). Methods Cancer tissues and normal lung tissues (>5 cm adjacent to cancer tissue) were collected from Chinese Han patients with NSCLC. Expression levels of SIRT6 and histone H3-acetyl K56 ( H3K56), in cancer and normal lung tissues from patients with NSCLC, were detected by reverse-transcription polymerase chain reaction, Western blot and immunohistochemistry...
January 1, 2018: Journal of International Medical Research
Yibo Li, Xue Li, Allison Cole, Sarah McLaughlin, Wei Du
Icraiin (ICA) is a flavonoid glucoside derived from the Epimedium plant genus, which has potent regenerative properties and is used in western medicine to treat impotence. Recently, ICA has generated great interest in improving hepatic stellate cell function and cardiac rejuvenation. However, how this natural component functions in hematopoiesis remains unexplored. Here we have examined the role of ICA on hematopoietic stem cells (HSCs) using the cancer-prone disease model of Fanconi anemia (FA), an inherited bone marrow failure syndrome with extremely high risk of leukemic predisposition...
January 22, 2018: Cell Cycle
Jian Chen, Jun-Jun Xie, Meng-Yun Jin, Yun-Tao Gu, Cong-Cong Wu, Wei-Jun Guo, Ying-Zhao Yan, Zeng-Jie Zhang, Jian-Le Wang, Xiao-Lei Zhang, Yan Lin, Jia-Li Sun, Guang-Hui Zhu, Xiang-Yang Wang, Yao-Sen Wu
Treatment of intervertebral disc degeneration (IDD) seeks to prevent senescence and death of nucleus pulposus (NP) cells. Previous studies have shown that sirt6 exerts potent anti-senescent and anti-apoptotic effects in models of age-related degenerative disease. However, it is not known whether sirt6 protects against IDD. Here, we explored whether sirt6 influenced IDD. The sirt6 level was reduced in senescent human NP cells. Sirt6 overexpression protected against apoptosis and both replicative and stress-induced premature senescence...
January 19, 2018: Cell Death & Disease
Kunhua Qin, Ning Zhang, Zhao Zhang, Michael Nipper, Zhenxin Zhu, Jake Leighton, Kexin Xu, Nicolas Musi, Pei Wang
AIMS/HYPOTHESIS: Better understanding of how genetic and epigenetic components control beta cell differentiation and function is key to the discovery of novel therapeutic approaches to prevent beta cell dysfunction and failure in the progression of type 2 diabetes. Our goal was to elucidate the role of histone deacetylase sirtuin 6 (SIRT6) in beta cell development and homeostasis. METHODS: Sirt6 endocrine progenitor cell conditional knockout and beta cell-specific knockout mice were generated using the Cre-loxP system...
January 10, 2018: Diabetologia
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