Linking Cancer Metabolism to DNA Repair and Accelerated Senescence
Conventional wisdom ascribes metabolic reprogramming in cancer to meeting increased demands for intermediates to support rapid proliferation. Prior models have proposed benefits toward cell survival, immortality, and stress resistance, although the recent discovery of oncometabolites has shifted att...
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Veröffentlicht in: | Molecular cancer research 2016-02, Vol.14 (2), p.173-184 |
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creator | Efimova, Elena V Takahashi, Satoe Shamsi, Noumaan A Wu, Ding Labay, Edwardine Ulanovskaya, Olesya A Weichselbaum, Ralph R Kozmin, Sergey A Kron, Stephen J |
description | Conventional wisdom ascribes metabolic reprogramming in cancer to meeting increased demands for intermediates to support rapid proliferation. Prior models have proposed benefits toward cell survival, immortality, and stress resistance, although the recent discovery of oncometabolites has shifted attention to chromatin targets affecting gene expression. To explore further effects of cancer metabolism and epigenetic deregulation, DNA repair kinetics were examined in cells treated with metabolic intermediates, oncometabolites, and/or metabolic inhibitors by tracking resolution of double-strand breaks (DSB) in irradiated MCF7 breast cancer cells. Disrupting cancer metabolism revealed roles for both glycolysis and glutaminolysis in promoting DSB repair and preventing accelerated senescence after irradiation. Targeting pathways common to glycolysis and glutaminolysis uncovered opposing effects of the hexosamine biosynthetic pathway (HBP) and tricarboxylic acid (TCA) cycle. Treating cells with the HBP metabolite N-acetylglucosamine (GlcNAc) or augmenting protein O-GlcNAcylation with small molecules or RNAi targeting O-GlcNAcase each enhanced DSB repair, while targeting O-GlcNAc transferase reversed GlcNAc's effects. Opposing the HBP, TCA metabolites including α-ketoglutarate blocked DSB resolution. Strikingly, DNA repair could be restored by the oncometabolite 2-hydroxyglutarate (2-HG). Targeting downstream effectors of histone methylation and demethylation implicated the PRC1/2 polycomb complexes as the ultimate targets for metabolic regulation, reflecting known roles for Polycomb group proteins in nonhomologous end-joining DSB repair. Our findings that epigenetic effects of cancer metabolic reprogramming may promote DNA repair provide a molecular mechanism by which deregulation of metabolism may not only support cell growth but also maintain cell immortality, drive therapeutic resistance, and promote genomic instability.
By defining a pathway from deregulated metabolism to enhanced DNA damage response in cancer, these data provide a rationale for targeting downstream epigenetic effects of metabolic reprogramming to block cancer cell immortality and overcome resistance to genotoxic stress. |
doi_str_mv | 10.1158/1541-7786.MCR-15-0263 |
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By defining a pathway from deregulated metabolism to enhanced DNA damage response in cancer, these data provide a rationale for targeting downstream epigenetic effects of metabolic reprogramming to block cancer cell immortality and overcome resistance to genotoxic stress.</description><identifier>ISSN: 1541-7786</identifier><identifier>EISSN: 1557-3125</identifier><identifier>DOI: 10.1158/1541-7786.MCR-15-0263</identifier><identifier>PMID: 26538285</identifier><language>eng</language><publisher>United States</publisher><subject>Acetylglucosamine - pharmacology ; Cellular Senescence ; DNA - radiation effects ; DNA Repair ; Epigenesis, Genetic ; Genomic Instability ; Glutamine - metabolism ; Glycolysis - drug effects ; Humans ; MCF-7 Cells ; Neoplasms - genetics ; Neoplasms - metabolism ; RNA Interference</subject><ispartof>Molecular cancer research, 2016-02, Vol.14 (2), p.173-184</ispartof><rights>2015 American Association for Cancer Research.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c463t-8393c1f90b027fae944355b6122283960de60d8b297d2a83214b6319e2a82db3</citedby><cites>FETCH-LOGICAL-c463t-8393c1f90b027fae944355b6122283960de60d8b297d2a83214b6319e2a82db3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,3356,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26538285$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Efimova, Elena V</creatorcontrib><creatorcontrib>Takahashi, Satoe</creatorcontrib><creatorcontrib>Shamsi, Noumaan A</creatorcontrib><creatorcontrib>Wu, Ding</creatorcontrib><creatorcontrib>Labay, Edwardine</creatorcontrib><creatorcontrib>Ulanovskaya, Olesya A</creatorcontrib><creatorcontrib>Weichselbaum, Ralph R</creatorcontrib><creatorcontrib>Kozmin, Sergey A</creatorcontrib><creatorcontrib>Kron, Stephen J</creatorcontrib><title>Linking Cancer Metabolism to DNA Repair and Accelerated Senescence</title><title>Molecular cancer research</title><addtitle>Mol Cancer Res</addtitle><description>Conventional wisdom ascribes metabolic reprogramming in cancer to meeting increased demands for intermediates to support rapid proliferation. Prior models have proposed benefits toward cell survival, immortality, and stress resistance, although the recent discovery of oncometabolites has shifted attention to chromatin targets affecting gene expression. To explore further effects of cancer metabolism and epigenetic deregulation, DNA repair kinetics were examined in cells treated with metabolic intermediates, oncometabolites, and/or metabolic inhibitors by tracking resolution of double-strand breaks (DSB) in irradiated MCF7 breast cancer cells. Disrupting cancer metabolism revealed roles for both glycolysis and glutaminolysis in promoting DSB repair and preventing accelerated senescence after irradiation. Targeting pathways common to glycolysis and glutaminolysis uncovered opposing effects of the hexosamine biosynthetic pathway (HBP) and tricarboxylic acid (TCA) cycle. Treating cells with the HBP metabolite N-acetylglucosamine (GlcNAc) or augmenting protein O-GlcNAcylation with small molecules or RNAi targeting O-GlcNAcase each enhanced DSB repair, while targeting O-GlcNAc transferase reversed GlcNAc's effects. Opposing the HBP, TCA metabolites including α-ketoglutarate blocked DSB resolution. Strikingly, DNA repair could be restored by the oncometabolite 2-hydroxyglutarate (2-HG). Targeting downstream effectors of histone methylation and demethylation implicated the PRC1/2 polycomb complexes as the ultimate targets for metabolic regulation, reflecting known roles for Polycomb group proteins in nonhomologous end-joining DSB repair. Our findings that epigenetic effects of cancer metabolic reprogramming may promote DNA repair provide a molecular mechanism by which deregulation of metabolism may not only support cell growth but also maintain cell immortality, drive therapeutic resistance, and promote genomic instability.
By defining a pathway from deregulated metabolism to enhanced DNA damage response in cancer, these data provide a rationale for targeting downstream epigenetic effects of metabolic reprogramming to block cancer cell immortality and overcome resistance to genotoxic stress.</description><subject>Acetylglucosamine - pharmacology</subject><subject>Cellular Senescence</subject><subject>DNA - radiation effects</subject><subject>DNA Repair</subject><subject>Epigenesis, Genetic</subject><subject>Genomic Instability</subject><subject>Glutamine - metabolism</subject><subject>Glycolysis - drug effects</subject><subject>Humans</subject><subject>MCF-7 Cells</subject><subject>Neoplasms - genetics</subject><subject>Neoplasms - metabolism</subject><subject>RNA Interference</subject><issn>1541-7786</issn><issn>1557-3125</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkMtOwzAQRS0EoqXwCSAv2aT4ET-yQSrhKbUgle4tJ5mUQJoUO0Xi73HUUsHCskdz753xQeickjGlQl9REdNIKS3Hs3QeURERJvkBGlIhVMQpE4f9e6cZoBPv3wlhhCp5jAZMCq6ZFkN0M62aj6pZ4tQ2OTg8g85mbV35Fe5afPs8wXNY28ph2xR4kudQg7MdFPgVGvA5BNMpOipt7eFsd4_Q4v5ukT5G05eHp3QyjfJY8i7SPOE5LROSEaZKC0kccyEySRljoSdJAeHojCWqYFZzRuNMcppAKFiR8RG63sauN9kKijC6c7Y2a1etrPs2ra3M_05TvZll-2ViJYTWMgRc7gJc-7kB35lVFX5Q17aBduNNQCMSqpgSQSq20ty13jso92MoMT1-06M1PVoT8IfK9PiD7-LvjnvXL2_-A2ERf_U</recordid><startdate>20160201</startdate><enddate>20160201</enddate><creator>Efimova, Elena V</creator><creator>Takahashi, Satoe</creator><creator>Shamsi, Noumaan A</creator><creator>Wu, Ding</creator><creator>Labay, Edwardine</creator><creator>Ulanovskaya, Olesya A</creator><creator>Weichselbaum, Ralph R</creator><creator>Kozmin, Sergey A</creator><creator>Kron, Stephen J</creator><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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20160201</creationdate><title>Linking Cancer Metabolism to DNA Repair and Accelerated Senescence</title><author>Efimova, Elena V ; Takahashi, Satoe ; Shamsi, Noumaan A ; Wu, Ding ; Labay, Edwardine ; Ulanovskaya, Olesya A ; Weichselbaum, Ralph R ; Kozmin, Sergey A ; Kron, Stephen J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c463t-8393c1f90b027fae944355b6122283960de60d8b297d2a83214b6319e2a82db3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Acetylglucosamine - pharmacology</topic><topic>Cellular Senescence</topic><topic>DNA - radiation effects</topic><topic>DNA Repair</topic><topic>Epigenesis, Genetic</topic><topic>Genomic Instability</topic><topic>Glutamine - metabolism</topic><topic>Glycolysis - drug effects</topic><topic>Humans</topic><topic>MCF-7 Cells</topic><topic>Neoplasms - genetics</topic><topic>Neoplasms - metabolism</topic><topic>RNA Interference</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Efimova, Elena V</creatorcontrib><creatorcontrib>Takahashi, Satoe</creatorcontrib><creatorcontrib>Shamsi, Noumaan A</creatorcontrib><creatorcontrib>Wu, Ding</creatorcontrib><creatorcontrib>Labay, Edwardine</creatorcontrib><creatorcontrib>Ulanovskaya, Olesya A</creatorcontrib><creatorcontrib>Weichselbaum, Ralph R</creatorcontrib><creatorcontrib>Kozmin, Sergey A</creatorcontrib><creatorcontrib>Kron, Stephen J</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Molecular cancer research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Efimova, Elena V</au><au>Takahashi, Satoe</au><au>Shamsi, Noumaan A</au><au>Wu, Ding</au><au>Labay, Edwardine</au><au>Ulanovskaya, Olesya A</au><au>Weichselbaum, Ralph R</au><au>Kozmin, Sergey A</au><au>Kron, Stephen J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Linking Cancer Metabolism to DNA Repair and Accelerated Senescence</atitle><jtitle>Molecular cancer research</jtitle><addtitle>Mol Cancer Res</addtitle><date>2016-02-01</date><risdate>2016</risdate><volume>14</volume><issue>2</issue><spage>173</spage><epage>184</epage><pages>173-184</pages><issn>1541-7786</issn><eissn>1557-3125</eissn><abstract>Conventional wisdom ascribes metabolic reprogramming in cancer to meeting increased demands for intermediates to support rapid proliferation. Prior models have proposed benefits toward cell survival, immortality, and stress resistance, although the recent discovery of oncometabolites has shifted attention to chromatin targets affecting gene expression. To explore further effects of cancer metabolism and epigenetic deregulation, DNA repair kinetics were examined in cells treated with metabolic intermediates, oncometabolites, and/or metabolic inhibitors by tracking resolution of double-strand breaks (DSB) in irradiated MCF7 breast cancer cells. Disrupting cancer metabolism revealed roles for both glycolysis and glutaminolysis in promoting DSB repair and preventing accelerated senescence after irradiation. Targeting pathways common to glycolysis and glutaminolysis uncovered opposing effects of the hexosamine biosynthetic pathway (HBP) and tricarboxylic acid (TCA) cycle. Treating cells with the HBP metabolite N-acetylglucosamine (GlcNAc) or augmenting protein O-GlcNAcylation with small molecules or RNAi targeting O-GlcNAcase each enhanced DSB repair, while targeting O-GlcNAc transferase reversed GlcNAc's effects. Opposing the HBP, TCA metabolites including α-ketoglutarate blocked DSB resolution. Strikingly, DNA repair could be restored by the oncometabolite 2-hydroxyglutarate (2-HG). Targeting downstream effectors of histone methylation and demethylation implicated the PRC1/2 polycomb complexes as the ultimate targets for metabolic regulation, reflecting known roles for Polycomb group proteins in nonhomologous end-joining DSB repair. Our findings that epigenetic effects of cancer metabolic reprogramming may promote DNA repair provide a molecular mechanism by which deregulation of metabolism may not only support cell growth but also maintain cell immortality, drive therapeutic resistance, and promote genomic instability.
By defining a pathway from deregulated metabolism to enhanced DNA damage response in cancer, these data provide a rationale for targeting downstream epigenetic effects of metabolic reprogramming to block cancer cell immortality and overcome resistance to genotoxic stress.</abstract><cop>United States</cop><pmid>26538285</pmid><doi>10.1158/1541-7786.MCR-15-0263</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Acetylglucosamine - pharmacology Cellular Senescence DNA - radiation effects DNA Repair Epigenesis, Genetic Genomic Instability Glutamine - metabolism Glycolysis - drug effects Humans MCF-7 Cells Neoplasms - genetics Neoplasms - metabolism RNA Interference |
title | Linking Cancer Metabolism to DNA Repair and Accelerated Senescence |
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