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https://www.readbyqxmd.com/read/29021282/methionine-metabolism-is-essential-for-sirt1-regulated-mouse-embryonic-stem-cell-maintenance-and-embryonic-development
#1
Shuang Tang, Yi Fang, Gang Huang, Xiaojiang Xu, Elizabeth Padilla-Banks, Wei Fan, Qing Xu, Sydney M Sanderson, Julie F Foley, Scotty Dowdy, Michael W McBurney, David C Fargo, Carmen J Williams, Jason W Locasale, Ziqiang Guan, Xiaoling Li
Methionine metabolism is critical for epigenetic maintenance, redox homeostasis, and animal development. However, the regulation of methionine metabolism remains unclear. Here, we provide evidence that SIRT1, the most conserved mammalian NAD(+)-dependent protein deacetylase, is critically involved in modulating methionine metabolism, thereby impacting maintenance of mouse embryonic stem cells (mESCs) and subsequent embryogenesis. We demonstrate that SIRT1-deficient mESCs are hypersensitive to methionine restriction/depletion-induced differentiation and apoptosis, primarily due to a reduced conversion of methionine to S-adenosylmethionine...
October 11, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28943955/p53-inhibits-the-upregulation-of-sirtuin-1-expression-induced-by-c-myc
#2
Fang Yuan, Lu Liu, Yonghong Lei, Peifu Tang
Sirtuin 1 (Sirt1), a conserved NAD(+) dependent deacetylase, is a mediator of life span by calorie restriction. However, Sirt1 may paradoxically increase the risk of cancer. Accordingly, the expression level of Sirt1 is selectively elevated in numerous types of cancer cell; however, the mechanisms underlying the differential regulation remain largely unknown. The present study demonstrated that oncoprotein c-Myc was a direct regulator of Sirt1, which accounts for the upregulation of Sirt1 expression only in the cells without functional p53...
October 2017: Oncology Letters
https://www.readbyqxmd.com/read/28863281/aging-related-decline-in-the-induction-of-nrf2-regulated-antioxidant-genes-in-human-bronchial-epithelial-cells
#3
Lulu Zhou, Hongqiao Zhang, Kelvin J A Davies, Henry Jay Forman
Evidence from animal studies suggests that stress-induced increases in Nrf2-regulated antioxidant gene expression, a critical mechanism of cellular protection, declines with aging. This study examined whether this also occurs in humans. We measured the basal and inducible levels of Nrf2-regulated antioxidant genes in human bronchial epithelial (HBE) cells from subjects of young adult (21-29 years) and older (60-69 years) non-smokers, and explored factors affecting expresion. The basal expression of three representative Nrf2-regulated genes, the catalytic and modulator subunits of glutamate cysteine ligase (GCLC and GCLM, respectively), and NAD(P)H quinone oxidoreductase 1 (NQO1), was higher in cells from the older donors compared with cells from the young adult donors...
August 24, 2017: Redox Biology
https://www.readbyqxmd.com/read/28162896/haploinsufficiency-of-sirt1-enhances-glutamine-metabolism-and-promotes-cancer-development
#4
Natalie S X Ren, Ming Ji, Erik J Tokar, Evan L Busch, Xiaojiang Xu, DeAsia Lewis, Xiangchun Li, Aiwen Jin, Yanping Zhang, William K K Wu, Weichun Huang, Leping Li, David C Fargo, Temitope O Keku, Robert S Sandler, Xiaoling Li
SIRT1, the most conserved mammalian NAD(+)-dependent protein deacetylase, plays a vital role in the regulation of metabolism, stress responses, and genome stability. However, the role of SIRT1 in the multi-step process leading to transformation and/or tumorigenesis, as either a tumor suppressor or tumor promoter, is complex and may be dependent upon the context in which SIRT1 activity is altered, and the role of SIRT1 in tumor metabolism is unknown. Here, we demonstrate that SIRT1 dose-dependently regulates cellular glutamine metabolism and apoptosis, which in turn differentially impact cell proliferation and cancer development...
February 20, 2017: Current Biology: CB
https://www.readbyqxmd.com/read/28122227/protection-against-high-fat-diet-induced-obesity-in-mdm2-c305f-mice-due-to-reduced-p53-activity-and-enhanced-energy-expenditure
#5
Shijie Liu, Tae-Hyung Kim, Derek A Franklin, Yanping Zhang
The RPL11-MDM2 interaction constitutes a p53 signaling pathway activated by deregulated ribosomal biosynthesis in response to stress. Mice bearing an MDM2(C305F) mutation that disrupts RPL11-MDM2 binding were analyzed on a high-fat diet (HFD). The Mdm2(C305F/C305F) mice, although phenotypically indistinguishable from wild-type (WT) mice when fed normal chow, demonstrated decreased fat accumulation along with improved insulin sensitivity and glucose tolerance after prolonged HFD feeding. We found that HFD increases expression of c-MYC and RPL11 in both WT and Mdm2(C305F/C305F) mice; however, p53 was induced in WT but not in Mdm2(C305F/C305F) mice...
January 24, 2017: Cell Reports
https://www.readbyqxmd.com/read/27725455/identification-of-a-selective-sirt2-inhibitor-and-its-anti-breast-cancer-activity
#6
Asad Ali Shah, Akihiro Ito, Akiko Nakata, Minoru Yoshida
SIRT2 is a member of the human sirtuin family of proteins and possesses nicotinamide adenine dinucleotide (NAD)-dependent lysine deacetylase activity. SIRT2 has been involved in various cellular processes including gene transcription, genome constancy, and the cell cycle. In addition, SIRT2 is deeply implicated in diverse diseases including cancer. In this study, we identified a small molecule inhibitor of SIRT2 with a structure different from known SIRT2 inhibitors by screening from a chemical library. The hit compound showed a high selectivity toward SIRT2 as it only inhibited SIRT2, and not other sirtuins including SIRT1 and SIRT3 or zinc-dependent histone deacetylases (HDACs) including HDAC1 and HDAC6, in vitro...
2016: Biological & Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/27390344/dual-and-specific-inhibition-of-nampt-and-pak4-by-kpt-9274-decreases-kidney-cancer-growth
#7
Omran Abu Aboud, Ching-Hsien Chen, William Senapedis, Erkan Baloglu, Christian Argueta, Robert H Weiss
Kidney cancer (or renal cell carcinoma, RCC) is the sixth most common malignancy in the United States and one of the relatively few whose incidence is increasing. Because of the near universal resistance which occurs with the use of current treatment regimens, reprogrammed metabolic pathways are being investigated as potential targets for novel therapies of this disease. Borrowing from studies on other malignancies, we have identified the PAK4 and NAD biosynthetic pathways as being essential for RCC growth...
September 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27180906/sirt6-suppresses-pancreatic-cancer-through-control-of-lin28b
#8
Sita Kugel, Carlos Sebastián, Julien Fitamant, Kenneth N Ross, Supriya K Saha, Esha Jain, Adrianne Gladden, Kshitij S Arora, Yasutaka Kato, Miguel N Rivera, Sridhar Ramaswamy, Ruslan I Sadreyev, Alon Goren, Vikram Deshpande, Nabeel Bardeesy, Raul Mostoslavsky
Chromatin remodeling proteins are frequently dysregulated in human cancer, yet little is known about how they control tumorigenesis. Here, we uncover an epigenetic program mediated by the NAD(+)-dependent histone deacetylase Sirtuin 6 (SIRT6) that is critical for suppression of pancreatic ductal adenocarcinoma (PDAC), one of the most lethal malignancies. SIRT6 inactivation accelerates PDAC progression and metastasis via upregulation of Lin28b, a negative regulator of the let-7 microRNA. SIRT6 loss results in histone hyperacetylation at the Lin28b promoter, Myc recruitment, and pronounced induction of Lin28b and downstream let-7 target genes, HMGA2, IGF2BP1, and IGF2BP3...
June 2, 2016: Cell
https://www.readbyqxmd.com/read/27076630/myc-driven-glycolysis-is-a-therapeutic-target-in-glioblastoma
#9
Kensuke Tateishi, A John Iafrate, Quan Ho, William T Curry, Tracy T Batchelor, Keith T Flaherty, Maristela L Onozato, Nina Lelic, Sudhandra Sundaram, Daniel P Cahill, Andrew S Chi, Hiroaki Wakimoto
PURPOSE: Deregulated Myc drives an oncogenic metabolic state, including pseudohypoxic glycolysis, adapted for the constitutive production of biomolecular precursors to feed rapid tumor cell growth. In glioblastoma, Myc facilitates renewal of the tumor-initiating cell reservoir contributing to tumor maintenance. We investigated whether targeting the Myc-driven metabolic state could be a selectively toxic therapeutic strategy for glioblastoma. EXPERIMENTAL DESIGN: The glycolytic dependency of Myc-driven glioblastoma was tested using (13)C metabolic flux analysis, glucose-limiting culture assays, and glycolysis inhibitors, including inhibitors of the NAD(+) salvage enzyme nicotinamide phosphoribosyl-transferase (NAMPT), in MYC and MYCN shRNA knockdown and lentivirus overexpression systems and in patient-derived glioblastoma tumorspheres with and without MYC/MYCN amplification...
September 1, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/26898756/a-crucial-role-of-sumoylation-in-modulating-sirt6-deacetylation-of-h3-at-lysine-56-and-its-tumor-suppressive-activity
#10
J Cai, Y Zuo, T Wang, Y Cao, R Cai, F-L Chen, J Cheng, J Mu
Sirt6 is a histone deacetylase with NAD(+)-dependent activity. Sirt6 has been shown as a tumor suppressor partially via inhibiting the expression of c-Myc target genes and ribosome biogenesis. However, how to regulate Sirt6 activity is largely unknown. In this study, we identify that Sirt6 can be modified by small ubiquitin-like modifier. Sirt6 SUMOylation deficiency specifically decreases its deacetylation of H3K56 but not H3K9 in vivo. Mechanistically, we find that SUMOylation deficiency decreases Sirt6 binding with c-Myc, decreasing Sirt6 occupancy on the locus of c-Myc target genes...
September 15, 2016: Oncogene
https://www.readbyqxmd.com/read/26655722/sirt1-limits-adipocyte-hyperplasia-through-c-myc-inhibition
#11
Houari Abdesselem, Aisha Madani, Ahmad Hani, Muna Al-Noubi, Neha Goswami, Hisham Ben Hamidane, Anja M Billing, Jennifer Pasquier, Michael S Bonkowski, Najeeb Halabi, Rajaa Dalloul, Mohamed Z Sheriff, Nasrin Mesaeli, Mohamed ElRayess, David A Sinclair, Johannes Graumann, Nayef A Mazloum
The expansion of fat mass in the obese state is due to increased adipocyte hypertrophy and hyperplasia. The molecular mechanism that drives adipocyte hyperplasia remains unknown. The NAD(+)-dependent protein deacetylase sirtuin 1 (SIRT1), a key regulator of mammalian metabolism, maintains proper metabolic functions in many tissues, counteracting obesity. Here we report that differentiated adipocytes are hyperplastic when SIRT1 is knocked down stably in mouse 3T3-L1 preadipocytes. This phenotype is associated with dysregulated adipocyte metabolism and enhanced inflammation...
January 29, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/25940188/sox2-deacetylation-by-sirt1-is-involved-in-mouse-somatic-reprogramming
#12
Wen-Li Mu, Ya-Jun Wang, Peng Xu, De-Long Hao, Xiu-Zhen Liu, Ting-Ting Wang, Feng Chen, Hou-Zao Chen, Xiang Lv, De-Pei Liu
Mouse somatic cells can be reprogrammed into induced pluripotent stem cells by defined factors known to regulate pluripotency, including Oct4, Sox2, Klf4, and c-Myc. Together with Oct4, Sox2 plays a major role as a master endogenous pluripotent genes trigger in reprogramming. It has been reported that Sirtuin 1 (Sirt1), a member of the Sirtuin family of NAD(+) -dependent protein deacetylases, is involved in embryonic stem cell antioxidation, differentiation, and individual development. However, as a deacetylation enzyme, whether Sirt1 influences reprogramming through its post-translational modification function remains unknown...
July 2015: Stem Cells
https://www.readbyqxmd.com/read/25591797/diphenylene-iodonium-interferes-with-cell-cycle-progression-and-induces-apoptosis-by-modulating-nad-p-h-oxidase-ros-cell-cycle-regulatory-pathways-in-burkitt-s-lymphoma-cells
#13
Ya Ding, Wenjun Zhu, Rui Sun, Gang Yuan, Dongsheng Zhang, Yuhua Fan, Jian Sun
Infection with Epstein-Barr virus (EBV) and its encoded latent membrane protein 1 (LMP1) play oncogenic roles in Burkitt's lymphoma (BL). Flow cytometry was used to measure cellular reactive oxygen species (ROS) concentrations, and cellular lactate generation and diphenylene iodonium (DPI) cytotoxicity were determined by analyzing lactate concentrations and cell viability. We also measured NAD(P)H oxidase (NOX) activity. Reverse transcriptase PCR and qPCR assays were used to analyze LMP1 levels, and protein expression was measured by immunoblotting...
March 2015: Oncology Reports
https://www.readbyqxmd.com/read/25483087/inhibition-of-c-terminal-binding-protein-attenuates-transcription-factor-4-signaling-to-selectively-target-colon-cancer-stem-cells
#14
Jagrut Patel, Somesh Baranwal, Ian M Love, Nirmita J Patel, Steven R Grossman, Bhaumik B Patel
Selective targeting of cancer stem cells (CSCs), implicated in tumor relapse, holds great promise in the treatment of colorectal cancer. Overexpression of C-terminal binding protein (CtBP), an NADH dependent transcriptional regulator, is often observed in colon cancer. Of note, TCF-4 signaling is also up-regulated in colonic CSCs. We hypothesized that CtBP, whose dehydrogenase activity is amenable to pharmacological inhibition by 4-methylthio-2-oxobutyric acid (MTOB), positively regulates TCF-4 signaling, leading to CSC growth and self-renewal...
2014: Cell Cycle
https://www.readbyqxmd.com/read/25325377/cip2a-regulates-cancer-metabolism-and-creb-phosphorylation-in-non-small-cell-lung-cancer
#15
Bo Peng, Ningjing Lei, Yurong Chai, Edward K L Chan, Jian-Ying Zhang
The cancerous inhibitor of protein phosphatase 2A (CIP2A) is a recently characterized endogenous inhibitor of the phosphatase activity of protein phosphatase 2A (PP2A), which extends the half-life of oncogenic protein c-myc and promotes in vivo tumor growth. The function of CIP2A in cancer progression is still poorly understood. To uncover the underlying mechanism of CIP2A-mediated cell proliferation, we implemented a two-dimensional electrophoresis (2DE)-based proteomic approach to examine lung cancer cell H1299 with and without CIP2A...
January 2015: Molecular BioSystems
https://www.readbyqxmd.com/read/25280219/sirt1-activation-by-a-c-myc-oncogenic-network-promotes-the-maintenance-and-drug-resistance-of-human-flt3-itd-acute-myeloid-leukemia-stem-cells
#16
Ling Li, Tereza Osdal, Yinwei Ho, Sookhee Chun, Tinisha McDonald, Puneet Agarwal, Allen Lin, Su Chu, Jing Qi, Liang Li, Yao-Te Hsieh, Cedric Dos Santos, Hongfeng Yuan, Trung-Quang Ha, Mihaela Popa, Randi Hovland, Øystein Bruserud, Bjørn Tore Gjertsen, Ya-Huei Kuo, Wenyong Chen, Sonia Lain, Emmet McCormack, Ravi Bhatia
The FLT3-ITD mutation is frequently observed in acute myeloid leukemia (AML) and is associated with poor prognosis. In such patients, FLT3 tyrosine kinase inhibitors (TKIs) are only partially effective and do not eliminate the leukemia stem cells (LSCs) that are assumed to be the source of treatment failure. Here, we show that the NAD-dependent SIRT1 deacetylase is selectively overexpressed in primary human FLT3-ITD AML LSCs. This SIRT1 overexpression is related to enhanced expression of the USP22 deubiquitinase induced by c-MYC, leading to reduced SIRT1 ubiquitination and enhanced stability...
October 2, 2014: Cell Stem Cell
https://www.readbyqxmd.com/read/25223261/identification-of-oxidative-stress-and-responsive-genes-of-hepg2-cells-exposed-to-quinocetone-and-compared-with-its-metabolites
#17
COMPARATIVE STUDY
Keyu Zhang, Wenli Zheng, Haihong Zheng, Chunmei Wang, Mi Wang, Tao Li, Xiaoyang Wang, Lifang Zhang, Sui Xiao, Chenzhong Fei, Feiqun Xue
Quinocetone, a new quinoxaline 1,4-dioxide derivative used in food-producing animals in China, exerts genotoxic effects on HepG2 cells. It triggers significant cytotoxicity and genotoxicity in vitro, but the detailed mechanism by which quinocetone induces adverse biological effects is not yet known. We analyzed the mechanisms behind quinocetone intoxication by investigating oxidative stress based on non-enzymatic and enzymatic antioxidant activities, and by identifying differentially regulated genes of HepG2 cells exposed to quinocetone using polymerase chain reaction (PCR)-based suppression subtractive hybridization to illustrate the toxicity mechanism of quinocetone...
December 2014: Cell Biology and Toxicology
https://www.readbyqxmd.com/read/24936455/sirt1-is-necessary-for-proficient-telomere-elongation-and-genomic-stability-of-induced-pluripotent-stem-cells
#18
Maria Luigia De Bonis, Sagrario Ortega, Maria A Blasco
The NAD-dependent deacetylase SIRT1 is involved in chromatin silencing and genome stability. Elevated SIRT1 levels in embryonic stem cells also suggest a role for SIRT1 in pluripotency. Murine SIRT1 attenuates telomere attrition in vivo and is recruited at telomeres in induced pluripotent stem cells (iPSCs). Because telomere elongation is an iPSC hallmark, we set out to study the role of SIRT1 in pluripotency in the setting of murine embryonic fibroblasts reprogramming into iPSCs. We find that SIRT1 is required for efficient postreprogramming telomere elongation, and that this effect is mediated by a c-MYC-dependent regulation of the mTert gene...
May 6, 2014: Stem Cell Reports
https://www.readbyqxmd.com/read/24815186/targeting-eif4gi-translation-initiation-factor-affords-an-attractive-therapeutic-strategy-in-multiple-myeloma
#19
Oshrat Attar-Schneider, Liat Drucker, Victoria Zismanov, Shelly Tartakover-Matalon, Michael Lishner
BACKGROUND: Deregulation of protein synthesis is integral to the malignant phenotype and translation initiation is the rate limiting stage. Therefore, eIF4F translation initiation complex components are attractive therapeutic targets. METHODS: Protein lysates of myeloma cells (cell lines/patients' bone marrow samples) untreated/treated with bevacizumab were assayed for eIF4GI expression, regulation (NQO1/proteosome dependent fragmentation) (WB, Dicumarol, qPCR) and targets (WB)...
September 2014: Cellular Signalling
https://www.readbyqxmd.com/read/24526120/gerometabolites-the-pseudohypoxic-aging-side-of-cancer-oncometabolites
#20
Javier A Menendez, Tomás Alarcón, Jorge Joven
Oncometabolites are defined as small-molecule components (or enantiomers) of normal metabolism whose accumulation causes signaling dysregulation to establish a milieu that initiates carcinogenesis. In a similar manner, we propose the term "gerometabolites" to refer to small-molecule components of normal metabolism whose depletion causes signaling dysregulation to establish a milieu that drives aging. In an investigation of the pathogenic activities of the currently recognized oncometabolites R(-)-2-hydroxyglutarate (2-HG), fumarate, and succinate, which accumulate due to mutations in isocitrate dehydrogenases (IDH), fumarate hydratase (FH), and succinate dehydrogenase (SDH), respectively, we illustrate the fact that metabolic pseudohypoxia, the accumulation of hypoxia-inducible factor (HIFα) under normoxic conditions, and the subsequent Warburg-like reprogramming that shifts glucose metabolism from the oxidative pathway to aerobic glycolysis are the same mechanisms through which the decline of the "gerometabolite" nicotinamide adenine dinucleotide (NAD)(+) reversibly disrupts nuclear-mitochondrial communication and contributes to the decline in mitochondrial function with age...
2014: Cell Cycle
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