Arsenic-induced metabolic shift triggered by the loss of miR-199a-5p through Sp1-dependent DNA methylation

Inorganic arsenic is an environmental carcinogen that poses a major global public health risk. A high percentage of drinking water from wells in the U.S. contains higher-than-normal levels of arsenic, suggesting an increased risk of arsenic-induced deleterious effects. In addition to primary prevent...

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Veröffentlicht in:Toxicology and applied pharmacology 2019-09, Vol.378, p.114606-114606, Article 114606
Hauptverfasser: He, Jun, Liu, Weitao, Ge, Xin, Wang, Gao-Chan, Desai, Vilas, Wang, Shaomin, Mu, Wei, Bhardwaj, Vikas, Seifert, Erin, Liu, Ling-Zhi, Bhushan, Alok, Peiper, Stephen C., Jiang, Bing-Hua
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container_title Toxicology and applied pharmacology
container_volume 378
creator He, Jun
Liu, Weitao
Ge, Xin
Wang, Gao-Chan
Desai, Vilas
Wang, Shaomin
Mu, Wei
Bhardwaj, Vikas
Seifert, Erin
Liu, Ling-Zhi
Bhushan, Alok
Peiper, Stephen C.
Jiang, Bing-Hua
description Inorganic arsenic is an environmental carcinogen that poses a major global public health risk. A high percentage of drinking water from wells in the U.S. contains higher-than-normal levels of arsenic, suggesting an increased risk of arsenic-induced deleterious effects. In addition to primary preventive measures, therapeutic strategies need to effectively address and integrate multiple molecular mechanisms underlying arsenic-induced carcinogenesis. We previously showed that the loss of miR-199a-5p in arsenic-transformed cells is pivotal to promote arsenic-induced angiogenesis and tumor growth in lung epithelial cells. In this study, we further showed that subacute or chronic exposure to arsenic diminished miR-199a-5p levels largely due to DNA methylation, which was achieved by increased DNA methyltransferase-1 (DNMT1) activity, mediated by the formation of specific protein 1 (Sp1)/DNMT1 complex. In addition to the DNA hypermethylation, arsenic exposure also repressed miR-199a transcription through a transcriptional repressor Sp1. We further identified an association between miR-199a-5p repression and the arsenic-mediated energy metabolic shift, as reflected by mitochondria defects and a switch to glycolysis, in which a glycolytic enzyme pyruvate kinase 2 (PKM2) was a functional target of miR-199a-5p. Taken together, the repression of miR-199a-5p through both Sp1-dependent DNA methylation and Sp1 transcriptional repression promotes an arsenic-mediated metabolic shift from mitochondria respiration to aerobic glycolysis via PKM2. [Display omitted] •Sp-1-dependent DNA methylation contributes to arsenic-induced miR-199a-5p repression.•Loss of miR-199a-5p associates with an arsenic-mediated energy metabolic shift.•PKM2 is the key effector of miR-199a-5p to promote arsenic-induced glycolysis.•The study links the aberrant epigenetic changes to metabolic dysfunction in arsenic-mediated malignant transformation.
doi_str_mv 10.1016/j.taap.2019.114606
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A high percentage of drinking water from wells in the U.S. contains higher-than-normal levels of arsenic, suggesting an increased risk of arsenic-induced deleterious effects. In addition to primary preventive measures, therapeutic strategies need to effectively address and integrate multiple molecular mechanisms underlying arsenic-induced carcinogenesis. We previously showed that the loss of miR-199a-5p in arsenic-transformed cells is pivotal to promote arsenic-induced angiogenesis and tumor growth in lung epithelial cells. In this study, we further showed that subacute or chronic exposure to arsenic diminished miR-199a-5p levels largely due to DNA methylation, which was achieved by increased DNA methyltransferase-1 (DNMT1) activity, mediated by the formation of specific protein 1 (Sp1)/DNMT1 complex. In addition to the DNA hypermethylation, arsenic exposure also repressed miR-199a transcription through a transcriptional repressor Sp1. We further identified an association between miR-199a-5p repression and the arsenic-mediated energy metabolic shift, as reflected by mitochondria defects and a switch to glycolysis, in which a glycolytic enzyme pyruvate kinase 2 (PKM2) was a functional target of miR-199a-5p. Taken together, the repression of miR-199a-5p through both Sp1-dependent DNA methylation and Sp1 transcriptional repression promotes an arsenic-mediated metabolic shift from mitochondria respiration to aerobic glycolysis via PKM2. [Display omitted] •Sp-1-dependent DNA methylation contributes to arsenic-induced miR-199a-5p repression.•Loss of miR-199a-5p associates with an arsenic-mediated energy metabolic shift.•PKM2 is the key effector of miR-199a-5p to promote arsenic-induced glycolysis.•The study links the aberrant epigenetic changes to metabolic dysfunction in arsenic-mediated malignant transformation.</description><identifier>ISSN: 0041-008X</identifier><identifier>EISSN: 1096-0333</identifier><identifier>DOI: 10.1016/j.taap.2019.114606</identifier><identifier>PMID: 31170415</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Activation, Metabolic - drug effects ; Arsenic ; Arsenic - adverse effects ; Carcinogenesis - drug effects ; Cell Line ; DNA methylation ; DNA Methylation - drug effects ; Glycolysis ; Glycolysis - drug effects ; Humans ; MicroRNAs - genetics ; miR-199a-5p ; PKM2 ; Sp1 ; Sp1 Transcription Factor - genetics</subject><ispartof>Toxicology and applied pharmacology, 2019-09, Vol.378, p.114606-114606, Article 114606</ispartof><rights>2019 Elsevier Inc.</rights><rights>Copyright © 2019 Elsevier Inc. 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A high percentage of drinking water from wells in the U.S. contains higher-than-normal levels of arsenic, suggesting an increased risk of arsenic-induced deleterious effects. In addition to primary preventive measures, therapeutic strategies need to effectively address and integrate multiple molecular mechanisms underlying arsenic-induced carcinogenesis. We previously showed that the loss of miR-199a-5p in arsenic-transformed cells is pivotal to promote arsenic-induced angiogenesis and tumor growth in lung epithelial cells. In this study, we further showed that subacute or chronic exposure to arsenic diminished miR-199a-5p levels largely due to DNA methylation, which was achieved by increased DNA methyltransferase-1 (DNMT1) activity, mediated by the formation of specific protein 1 (Sp1)/DNMT1 complex. In addition to the DNA hypermethylation, arsenic exposure also repressed miR-199a transcription through a transcriptional repressor Sp1. We further identified an association between miR-199a-5p repression and the arsenic-mediated energy metabolic shift, as reflected by mitochondria defects and a switch to glycolysis, in which a glycolytic enzyme pyruvate kinase 2 (PKM2) was a functional target of miR-199a-5p. Taken together, the repression of miR-199a-5p through both Sp1-dependent DNA methylation and Sp1 transcriptional repression promotes an arsenic-mediated metabolic shift from mitochondria respiration to aerobic glycolysis via PKM2. [Display omitted] •Sp-1-dependent DNA methylation contributes to arsenic-induced miR-199a-5p repression.•Loss of miR-199a-5p associates with an arsenic-mediated energy metabolic shift.•PKM2 is the key effector of miR-199a-5p to promote arsenic-induced glycolysis.•The study links the aberrant epigenetic changes to metabolic dysfunction in arsenic-mediated malignant transformation.</description><subject>Activation, Metabolic - drug effects</subject><subject>Arsenic</subject><subject>Arsenic - adverse effects</subject><subject>Carcinogenesis - drug effects</subject><subject>Cell Line</subject><subject>DNA methylation</subject><subject>DNA Methylation - drug effects</subject><subject>Glycolysis</subject><subject>Glycolysis - drug effects</subject><subject>Humans</subject><subject>MicroRNAs - genetics</subject><subject>miR-199a-5p</subject><subject>PKM2</subject><subject>Sp1</subject><subject>Sp1 Transcription Factor - genetics</subject><issn>0041-008X</issn><issn>1096-0333</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kF2LEzEUhoO4uHX1D3gh-QOpOc3XBEQou37B4sKugnchTc50UqYzQyZd6L83pbrojVeBvOd9kvMQ8gb4Ejjod7tl8X5arjjYJYDUXD8jC-BWMy6EeE4WnEtgnDc_L8nLed5xzq2U8IJcCgBTM7Ugu3WecUiBpSEeAka6x-I3Y58CnbvUFlpy2m4x12RzpKVD2o_zTMeW7tM9A2s9U1O9z-Nh29GHCVjECYeIQ6E339YnXHfsfUnj8IpctL6f8fXv84r8-PTx-_UXdnv3-ev1-pYFqVRhTWxtVAaNXq0UeCWt0gIbtI0Ai1p5A1IaJbTgwI1Ujd1YHY0BrWIwGsQV-XDmTofNHmOoX8m-d1NOe5-PbvTJ_ZsMqXPb8dFp0zTGyApYnQEh110ztk9d4O5k3u3cybw7mXdn87X09u9Xnyp_VNeB9-cBrLs_JsxuDgmH6jxlDMXFMf2P_wtpmJRT</recordid><startdate>20190901</startdate><enddate>20190901</enddate><creator>He, Jun</creator><creator>Liu, Weitao</creator><creator>Ge, Xin</creator><creator>Wang, Gao-Chan</creator><creator>Desai, Vilas</creator><creator>Wang, Shaomin</creator><creator>Mu, Wei</creator><creator>Bhardwaj, Vikas</creator><creator>Seifert, Erin</creator><creator>Liu, Ling-Zhi</creator><creator>Bhushan, Alok</creator><creator>Peiper, Stephen C.</creator><creator>Jiang, Bing-Hua</creator><general>Elsevier Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>5PM</scope></search><sort><creationdate>20190901</creationdate><title>Arsenic-induced metabolic shift triggered by the loss of miR-199a-5p through Sp1-dependent DNA methylation</title><author>He, Jun ; 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We further identified an association between miR-199a-5p repression and the arsenic-mediated energy metabolic shift, as reflected by mitochondria defects and a switch to glycolysis, in which a glycolytic enzyme pyruvate kinase 2 (PKM2) was a functional target of miR-199a-5p. Taken together, the repression of miR-199a-5p through both Sp1-dependent DNA methylation and Sp1 transcriptional repression promotes an arsenic-mediated metabolic shift from mitochondria respiration to aerobic glycolysis via PKM2. [Display omitted] •Sp-1-dependent DNA methylation contributes to arsenic-induced miR-199a-5p repression.•Loss of miR-199a-5p associates with an arsenic-mediated energy metabolic shift.•PKM2 is the key effector of miR-199a-5p to promote arsenic-induced glycolysis.•The study links the aberrant epigenetic changes to metabolic dysfunction in arsenic-mediated malignant transformation.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>31170415</pmid><doi>10.1016/j.taap.2019.114606</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record>
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subjects Activation, Metabolic - drug effects
Arsenic
Arsenic - adverse effects
Carcinogenesis - drug effects
Cell Line
DNA methylation
DNA Methylation - drug effects
Glycolysis
Glycolysis - drug effects
Humans
MicroRNAs - genetics
miR-199a-5p
PKM2
Sp1
Sp1 Transcription Factor - genetics
title Arsenic-induced metabolic shift triggered by the loss of miR-199a-5p through Sp1-dependent DNA methylation
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