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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
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
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
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
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
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
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
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
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
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
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, Oystein 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
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
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
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
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
Andrew R Mendelsohn, James W Larrick
That some aging-associated phenotypes may be reversible is an emerging theme in contemporary aging research. Gomes et al. report that age-associated oxidative phosphorylation (OXPHOS) defects in murine skeletal muscle are biphasic. In the first phase, OXPHOS is decreased because of reduced expression of mitochondrially encoded genes. Treatment of moderately old mice (first-phase OXPHOS defects) with nicotinamide adenine dinucleotide (NAD⁺) precursor nicotinamide mononucleotide (NMN) for 1 week restores oxidative phosphorylation activity and other markers of mitochondrial function in skeletal muscle...
February 2014: Rejuvenation Research
Jiyung Shin, Ming He, Yufei Liu, Silvana Paredes, Lidia Villanova, Katharine Brown, Xiaolei Qiu, Noushin Nabavi, Mary Mohrin, Kathleen Wojnoonski, Patrick Li, Hwei-Ling Cheng, Andrew J Murphy, David M Valenzuela, Hanzhi Luo, Pankaj Kapahi, Ronald Krauss, Raul Mostoslavsky, George D Yancopoulos, Frederick W Alt, Katrin F Chua, Danica Chen
Nonalcoholic fatty liver disease is the most common chronic liver disorder in developed countries. Its pathogenesis is poorly understood, and therapeutic options are limited. Here, we show that SIRT7, an NAD(+)-dependent H3K18Ac deacetylase, functions at chromatin to suppress ER stress and prevent the development of fatty liver disease. SIRT7 is induced upon ER stress and is stabilized at the promoters of ribosomal proteins through its interaction with the transcription factor Myc to silence gene expression and to relieve ER stress...
November 14, 2013: Cell Reports
Jean-Pierre Etchegaray, Lei Zhong, Raul Mostoslavsky
SIRT6 is one of the seven members of the NAD-dependent family of sirtuins mammals. The pleotropic identity of SIRT6 is manifested into several catalytic activities such as deacetylation, deacylation and ribosylation, which allow the targeting of a variety of protein substrates, that influence the physiology of multiple cell types and tissues. SIRT6- dependent deacetylation of histone H3 at lysines 9 and 56 is required for the regulation of genes associated with glucose/ lipid metabolism as well as the maintenance of telomeric regions and the repair of DNA double strand breaks...
2013: Current Topics in Medicinal Chemistry
Marina Vettraino, Marcella Manerba, Marzia Govoni, Giuseppina Di Stefano
Activation of the myc oncogene in cancer cells upregulates lactate dehydrogenase A (LDH-A) expression, leading to a sustained glycolytic flux that is needed to produce ATP under hypoxic conditions. We studied the effects of galloflavin (GF), a recently identified LDH inhibitor, on myc overexpressing Burkitt lymphoma (BL) cells. Epstein-Barr virus-infected lymphoblasts were used as a non-neoplastic control. Our results showed that myc overactivation induced a two- to seven-fold increase in LDH-A expression in BL cells compared with non-neoplastic lymphoblasts; this result is consistent with previously reported data...
September 2013: Anti-cancer Drugs
Xia Zhou, Lucy X Fan, William E Sweeney, John M Denu, Ellis D Avner, Xiaogang Li
Autosomal-dominant polycystic kidney disease (ADPKD) is caused by mutations in either PKD1 or PKD2 and is characterized by the development of multiple bilateral renal cysts that replace normal kidney tissue. Here, we used Pkd1 mutant mouse models to demonstrate that the nicotinamide adenine dinucleotide-dependent (NAD-dependent) protein deacetylase sirtuin 1 (SIRT1) is involved in the pathophysiology of ADPKD. SIRT1 was upregulated through c-MYC in embryonic and postnatal Pkd1-mutant mouse renal epithelial cells and tissues and could be induced by TNF-α, which is present in cyst fluid during cyst development...
July 2013: Journal of Clinical Investigation
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