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Raghavendra Vadla, Devyani Haldar
Metabolic reprogramming is a hallmark of cancer cells, but the mechanisms are not well understood. The mammalian target of rapamycin complex 2 (mTORC2) controls cell growth and proliferation and plays a critical role in metabolic reprogramming in glioma. mTORC2 regulates cellular processes such as cell survival, metabolism, and proliferation by phosphorylation of AGC kinases. Components of mTORC2 are shown to localize to the nucleus, but whether mTORC2 modulates epigenetic modifications to regulate gene expression is not known...
November 16, 2017: Cell Cycle
Keila Lopes Mendes, Deborah de Farias Lelis, Sérgio Henrique Sousa Santos
The regulation of chronic inflammation has received considerable research attention in recent years because of its contribution to the pathogenesis of chronic diseases such as arthritis, diabetes, metabolic syndrome and obesity. Thus, strategies that inhibit the inflammatory state may be beneficial in improving the pathophysiology of several inflammation-related disorders. Sirtuins are a family of histone deacetylases that contain seven enzymatic activities in mammals (SIRT1-SIRT7) and function to suppress gene transcription by epigenetic mechanisms...
November 7, 2017: Cytokine & Growth Factor Reviews
Song Zhang, Shuai Jiang, Haiping Wang, Wencheng Di, Chao Deng, Zhenxiao Jin, Wei Yi, Xiao Xiao, Yongzhan Nie, Yang Yang
Silent information regulator 6 (SIRT6), a class III histone deacetylase, has been revealed to participate in multiple metabolic processes in the liver, and it plays important roles in protecting against ischemia/reperfusion (I/R) injury in multiple organs. In this study, we explored whether SIRT6 is protective against hepatic I/R injury and elucidated the underlying mechanisms. The expression of SIRT6 was significantly decreased during reperfusion compared with the control group. SIRT6-LKO mice exhibited significantly aggravated oxidative stress, mitochondrial dysfunction, inflammatory responses, mitogen-activated protein kinase (MAPK) signaling activation, and apoptosis and autophagy related hepatocyte death compared with control mice...
November 10, 2017: Free Radical Biology & Medicine
Libo Ruan, Jun Chen, Litao Ruan, Tianrui Yang, Ping Wang
MicroRNAs are a class of small non-coding RNA molecules that play crucial roles in the initiation and progression of lung cancer. This study was undertaken to investigate the expression and roles of miR-186 in lung cancer. Ectopic expression experiments demonstrated that miR-186 functions as a tumor suppressor. Bioinformatic predictions, a luciferase reporter assay, and protein expression analysis suggested that miR-186 could inhibit the protein levels of SIRT6, a purported tumor suppressor gene. Collectively, our results indicated that miR-186 could inhibit lung cancer progression through targeting SIRT6 and that miR-186 may be a therapeutic target for lung cancer...
November 3, 2017: Cancer Biomarkers: Section A of Disease Markers
Yadong Wang, Teng Pan, Haiyu Wang, Li Li, Jiangmin Li, Ding Zhang, Haiyan Yang
Objective: This study aimed to explore the effects of overexpression of sirtuin 6 (SIRT6) on the tumorigenicity of hepatocellular carcinoma (HCC) cells. Methods: Stable SIRT6-overexpressed HCC cell lines were established by transfecting SIRT6 plasmid. Soft agar assay and tumor xenograft assay in nude mice were applied. Flow cytometry was employed to detect cell cycle distribution. Western blotting analysis was used to detect the expression of proteins. Results: Overexpression of SIRT6 attenuated HepG2 and HCCLM3 cells proliferation, colony formation in vitro and tumor formation in nude mice, and resulted in the G1 phase cell cycle arrest...
September 29, 2017: Oncotarget
Vasily V Ashapkin, Lyudmila I Kutueva, Boris F Vanyushin
INTRODUCTION: Hypermethylation of genes associated with promoter CpG islands, and hypomethylation of CpG poor genes, repeat sequences, transposable elements and intergenic genome sections occur during aging in mammals. Methylation levels of certain CpG sites display strict correlation to age and could be used as "epigenetic clock" to predict biological age. Multi-substrate deacetylases SIRT1 and SIRT6 affect aging via locus-specific modulations of chromatin structure and activity of multiple regulatory proteins involved in aging...
October 2017: Current Genomics
Zhen-Zhou Zhang, Yu-Wen Cheng, Hai-Yan Jin, Qing Chang, Qian-Hui Shang, Ying-Le Xu, Lin-Xi Chen, Ran Xu, Bei Song, Jiu-Chang Zhong
Sirtuin 6 (SIRT6) is an important modulator of cardiovascular functions in health and diseases. However, the exact role of SIRT6 in heart disease is poorly defined. We hypothesized that SIRT6 is a negative regulator of angiotensin II (Ang II)-mediated myocardial remodeling, fibrosis and injury. The male Sprague-Dawley rats were randomized to Ang II (200 ng/kg/min) infusion with an osmotic minipump and pretreated with recombinant plasmids adeno-associated viral vector (AAV)-SIRT6 (pAAV-SIRT6) or pAAV-GFP for 4 weeks...
September 22, 2017: Oncotarget
María A Zorrilla-Zubilete, Ada Yeste, Francisco J Quintana, Debra Toiber, Raul Mostoslavsky, Dafne M Silberman
Diabetic retinopathy (DR) is one of the common complications associated with diabetes mellitus (DM) and the leading cause of blindness worldwide. Recent research has demonstrated that DR is not only a microvascular disease but may be a result of neurodegenerative processes. Moreover, glucose-induced neuron and glial cell damage may occur shortly after the onset of diabetes which makes the disease hard to diagnose at early stages. SIRT6, a NAD-dependent sirtuin deacylase, modulates aging, energy metabolism and neurodegeneration...
October 19, 2017: Journal of Neurochemistry
Antonia Cagnetta, Debora Soncini, Stefania Orecchioni, Giovanna Talarico, Paola Minetto, Fabio Guolo, Veronica Retali, Nicoletta Colombo, Enrico Carminati, Marino Clavio, Maurizio Miglino, Micaela Bergamaschi, Aimable Nahimana, Michael Duchosal, Katia Todoerti, Antonino Neri, Mario Passalacqua, Santina Bruzzone, Alessio Nencioni, Francesco Bertolini, Marco Gobbi, Roberto M Lemoli, Michele Cea
Genomic instability plays a pathological role in various malignancies, including acute myeloid leukemia, and thus represents potential therapeutic target. Recent studies demonstrate that SIRT6, a NAD+-dependent nuclear deacetylase, functions as genome-guardian by preserving DNA integrity in different tumor cells. Here, we demonstrate that also CD34+ blasts from Acute Myeloid Leukemia patients show ongoing DNA damage and SIRT6 overexpression. Indeed, we identified a poor-prognostic subset of patients, with widespread instability, which relies on SIRT6 to compensate for DNA-replication stress...
October 12, 2017: Haematologica
Karam Kim, Sungkwan An, Byung Gon Choi, Dahye Joo, Young Min Choi, Kyu Joong Ahn, In-Sook An, Hwa Jun Cha
Arctiin, a lignin isolated from Arctium lappa, exhibits a variety of biological effects, including anti‑viral, anti‑inflammatory, and anti‑proliferative actions, in mammalian cells. In a previous study, arctiin was demonstrated to induce procollagen type I synthesis and exhibited protective effects against ultraviolet B (UVB) radiation in normal human dermal fibroblasts (nHDFs). However, the underlying molecular mechanism of arctiin‑mediated collagen synthesis remains unknown. In the present study, the mechanism for increased expression of collagen type 1α 1 chain (COL1A1) mRNA in arctiin‑induced nHDFs was identified...
December 2017: Molecular Medicine Reports
Arang Kim, Wooje Lee, Jung-Mi Yun
BACKGROUND/OBJECTIVE: Chronic hyperglycemia induces oxidative stress via accumulation of reactive oxygen species (ROS) and contributes to diabetic complications. Hyperglycemia induces mitochondrial superoxide anion production through the increased activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. This study aimed to determine whether fisetin and luteolin treatments suppress the oxidative stress by modulating the expression of sirtuins (SIRTs) and forkhead box O3a (FOXO3a) under hyperglycemic conditions in human monocytes...
October 2017: Nutrition Research and Practice
Dahye Joo, Sungkwan An, Byung Gon Choi, Karam Kim, Young Min Choi, Kyu Joong Ahn, In-Sook An, Hwa Jun Cha
Ultraviolet (UV) light mediates skin aging and induces destruction of the dermis by modulating the expression levels of extracellular matrix‑associated genes, including collagen and matrix metalloproteinases. Sirtuin 6 (SIRT6), a member of the sirtuin family of proteins, regulates collagen metabolism and is an established anti‑aging protein. However, the exact underlying mechanism by which SIRT6 expression is regulated in dermal fibroblasts during the aging process is unclear. The present study demonstrated that expression of microRNA‑378b (miR‑378b) is induced in UVB‑exposed human dermal fibroblasts (HDFs), and this was inversely associated with the mRNA expression levels of α‑1‑type 1 collagen (COL1A1)...
December 2017: Molecular Medicine Reports
Kunming Tian, Panpan Chen, Zhiping Liu, Shutian Si, Qian Zhang, Yong Mou, Lianyong Han, Qin Wang, Xue Zhou
Sirt6 which is implicated in the control of aging, cancer, and metabolism, has been shown to have anti-fibrosis function in heart and liver. However, whether Sirt6 inhibits idiopathic pulmonary fibrosis remains elusive. Epithelial to mesenchymal transition has been found to be involved in the pathogenesis of idiopathic pulmonary fibrosis. In the present study, forced expression of Sirt6 significantly abrogated TGF-β1-induced epithelial to mesenchymal transition-like phenotype and cell behaviors in A549 cells...
September 22, 2017: Oncotarget
Patrizia Damonte, Giovanna Sociali, Marco Daniele Parenti, Debora Soncini, Inga Bauer, Silvia Boero, Alessia Grozio, Maria von Holtey, Francesco Piacente, Pamela Becherini, Roberta Sanguineti, Annalisa Salis, Gianluca Damonte, Michele Cea, Maximilien Murone, Alessandro Poggi, Alessio Nencioni, Alberto Del Rio, Santina Bruzzone
The NAD(+)-dependent deacetylase SIRT6 is an emerging cancer drug target, whose inhibition sensitizes cancer cells to chemo-radiotherapy and has pro-differentiating effects. Here we report on the identification of novel SIRT6 inhibitors with a salicylate-based structure. The new SIRT6 inhibitors show improved potency and specificity compared to the hit inhibitor identified in an in silico compound screen. As predicted based on SIRT6 biological roles, the new leads increase histone 3 lysine 9 acetylation and glucose uptake in cultured cells, while blocking TNF-α production and T lymphocyte proliferation...
September 19, 2017: Bioorganic & Medicinal Chemistry
Wei Zhang, Rui Wei, Lin Zhang, Yang Tan, Chuanyun Qian
Sirtuin 6 (SIRT6), a member of the sirtuin family of NAD(+)-dependent deacetylases, has been shown to produce beneficial effects in myocardial ischemia/reperfusion (I/R). However, the role of SIRT6 in cerebral I/R is largely unclear. In this study, we investigated the effects of SIRT6 overexpression in regulating I/R injury in a mouse cerebral I/R model in vivo and in oxygen-glucose-deprivation/reoxygenation (OGD/R)-stimulated neuro-2a neuroblastoma cells in vitro. We found that cerebral I/R (1 h/24 h) resulted in decreased SIRT6 expression in the cerebral cortex (P < 0...
September 23, 2017: Neuroscience
Ankita Singh, Ellora Sen
Emerging evidences suggest the impact of autophagy on differentiation but the underlying molecular links between metabolic restructuring and autophagy during monocyte differentiation remain elusive. An increase in PPARγ, HK2 and SIRT6 expression was observed upon PMA induced monocyte differentiation. While PPARγ positively regulated HK2 and SIRT6 expression, the latter served as a negative regulator of HK2. Changes in expression of these metabolic modelers were accompanied by decreased glucose uptake and increase in Chibby, a potent antagonist of β-catenin/Wnt pathway...
November 15, 2017: Experimental Cell Research
Seong Uk Jeh, Jung Je Park, Jong Sil Lee, Dong Chul Kim, Jungmo Do, Sin Woo Lee, See Min Choi, Jae Seog Hyun, Deok Ha Seo, Chunwoo Lee, Sung Chul Kam, Ky Hyun Chung, Jeong Seok Hwa
OBJECTIVES: Sirtuins (1-7) are evolutionarily conserved NAD-dependent deacetylases that play an important role in carcinogenesis. However, their role in renal cell carcinoma (RCC) remains unclear. The objective of the present study was to examine the role of SIRTs in RCC carcinogenesis and prognosis. MATERIALS AND METHODS: Paraffin-embedded specimens from 102 patients who underwent extirpative renal surgeries for renal masses between January 2004 and December 2010 were examined...
September 18, 2017: Urologic Oncology
Sadhana A Samant, Abhinav Kanwal, Vinodkumar B Pillai, Riyue Bao, Mahesh P Gupta
Muscle wasting, also known as cachexia, is associated with many chronic diseases, which worsens prognosis of primary illness leading to enhanced mortality. Molecular basis of this metabolic syndrome is not yet completely understood. SIRT6 is a chromatin-bound member of the sirtuin family, implicated in regulating many cellular processes, ranging from metabolism, DNA repair to aging. SIRT6 knockout (SIRT6-KO) mice display loss of muscle, fat and bone density, typical characteristics of cachexia. Here we report that SIRT6 depletion in cardiac as well as skeletal muscle cells promotes myostatin (Mstn) expression...
September 19, 2017: Scientific Reports
Fikret Rifatbegovic, Christian Frech, M Reza Abbasi, Sabine Taschner-Mandl, Tamara Weiss, Wolfgang M Schmidt, Iris Schmidt, Ruth Ladenstein, Inge M Ambros, Peter F Ambros
Neuroblastoma is the most common extracranial solid tumor in childhood. The vast majority of metastatic (M) stage patients present with disseminated tumor cells (DTCs) in the bone marrow (BM) at diagnosis and relapse. Although these cells represent a major obstacle in the treatment of neuroblastoma patients, insights into their expression profile remained elusive. The present RNA-Seq study of stage 4/M primary tumors, enriched BM-derived diagnostic and relapse DTCs, as well as the corresponding BM-derived mononuclear cells (MNCs) from 53 patients revealed 322 differentially expressed genes in DTCs as compared to the tumors (q < 0...
September 16, 2017: International Journal of Cancer. Journal International du Cancer
Hang Lin, Yi Hao, Zhengxu Zhao, Yongjun Tong
Dysregulation of sirtuin 6 (SIRT6) is actively involved in tumor progression. High levels of SIRT6 have been associated with hepatocellular carcinoma and non-small cell lung cancer, and SIRT6 facilitates growth and metastasis of cancer cells. However, the clinical significance and biological function of SIRT6 are not known for osteosarcoma (OS). Here, we report that SIRT6 was notably overexpressed in OS tissues compared with non-cancerous specimens. The high level of SIRT6 was prominently correlated with malignant clinical parameters and poor prognosis of OS patients...
September 2017: FEBS Open Bio
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