PMID- 31170415 OWN - NLM STAT- MEDLINE DCOM- 20200520 LR - 20231213 IS - 1096-0333 (Electronic) IS - 0041-008X (Print) IS - 0041-008X (Linking) VI - 378 DP - 2019 Sep 1 TI - Arsenic-induced metabolic shift triggered by the loss of miR-199a-5p through Sp1-dependent DNA methylation. PG - 114606 LID - S0041-008X(19)30208-X [pii] LID - 10.1016/j.taap.2019.114606 [doi] AB - 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. CI - Copyright (c) 2019 Elsevier Inc. All rights reserved. FAU - He, Jun AU - He J AD - Department of Pathology, Anatomy & Cell Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, United States of America. Electronic address: Jun.he@jefferson.edu. FAU - Liu, Weitao AU - Liu W AD - Department of Pathology, Nanjing Medical University, Nanjing, China. FAU - Ge, Xin AU - Ge X AD - Department of Pathology, Nanjing Medical University, Nanjing, China. FAU - Wang, Gao-Chan AU - Wang GC AD - Department of Pathology, Anatomy & Cell Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, United States of America. FAU - Desai, Vilas AU - Desai V AD - Department of Pharmaceutical Sciences, College of Pharmacy, Thomas Jefferson University, Philadelphia, PA 19107, United States of America. FAU - Wang, Shaomin AU - Wang S AD - Department of Pathology, Anatomy & Cell Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, United States of America. FAU - Mu, Wei AU - Mu W AD - School of Public Health, Shanghai Jiaotong University School of Medicine, Shanghai, China. FAU - Bhardwaj, Vikas AU - Bhardwaj V AD - Department of Pharmaceutical Sciences, College of Pharmacy, Thomas Jefferson University, Philadelphia, PA 19107, United States of America. FAU - Seifert, Erin AU - Seifert E AD - Department of Pathology, Anatomy & Cell Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, United States of America. FAU - Liu, Ling-Zhi AU - Liu LZ AD - Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IW 52242, United States of America. FAU - Bhushan, Alok AU - Bhushan A AD - Department of Pharmaceutical Sciences, College of Pharmacy, Thomas Jefferson University, Philadelphia, PA 19107, United States of America. FAU - Peiper, Stephen C AU - Peiper SC AD - Department of Pathology, Anatomy & Cell Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, United States of America. FAU - Jiang, Bing-Hua AU - Jiang BH AD - Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IW 52242, United States of America. Electronic address: bing-hua-jiang@uiowa.edu. LA - eng GR - R00 CA215316/CA/NCI NIH HHS/United States GR - R01 ES027901/ES/NIEHS NIH HHS/United States GR - P30 ES005605/ES/NIEHS NIH HHS/United States GR - P30 CA086862/CA/NCI NIH HHS/United States GR - R01 CA193511/CA/NCI NIH HHS/United States GR - R01 ES020868/ES/NIEHS NIH HHS/United States GR - R01 CA232587/CA/NCI NIH HHS/United States GR - K02 ES029119/ES/NIEHS NIH HHS/United States GR - K99 CA215316/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20190603 PL - United States TA - Toxicol Appl Pharmacol JT - Toxicology and applied pharmacology JID - 0416575 RN - 0 (MicroRNAs) RN - 0 (Sp1 Transcription Factor) RN - 0 (SP1 protein, human) RN - 0 (mirn199 microRNA, human) RN - N712M78A8G (Arsenic) SB - IM MH - Activation, Metabolic/drug effects MH - Arsenic/*adverse effects MH - Carcinogenesis/drug effects MH - Cell Line MH - DNA Methylation/*drug effects MH - Glycolysis/drug effects MH - Humans MH - MicroRNAs/*genetics MH - Sp1 Transcription Factor/*genetics PMC - PMC6788774 MID - NIHMS1533091 OTO - NOTNLM OT - Arsenic OT - DNA methylation OT - Glycolysis OT - PKM2 OT - Sp1 OT - miR-199a-5p COIS- Declaration of Conflicting interests The authors declare no potential conflicts of interest. Conflicts of Interest Statement All authors declare no potential conflicts of interest. EDAT- 2019/06/07 06:00 MHDA- 2020/05/21 06:00 PMCR- 2020/09/01 CRDT- 2019/06/07 06:00 PHST- 2019/02/11 00:00 [received] PHST- 2019/05/21 00:00 [revised] PHST- 2019/05/31 00:00 [accepted] PHST- 2019/06/07 06:00 [pubmed] PHST- 2020/05/21 06:00 [medline] PHST- 2019/06/07 06:00 [entrez] PHST- 2020/09/01 00:00 [pmc-release] AID - S0041-008X(19)30208-X [pii] AID - 10.1016/j.taap.2019.114606 [doi] PST - ppublish SO - Toxicol Appl Pharmacol. 2019 Sep 1;378:114606. doi: 10.1016/j.taap.2019.114606. Epub 2019 Jun 3.