Genetic and epigenetic modeling of the origins of multidrug-resistant cells in a human sarcoma cell line
The origin of drug-resistant cells in human cancers has been a fundamental problem of cancer pharmacology. Two major contrasting hypotheses (genetics versus epigenetics) have been proposed to elucidate the mechanisms of acquired drug resistance. In this study, we answer these fundamental questions t...
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| Veröffentlicht in: | Cancer research (Chicago, Ill.) Ill.), 2005-10, Vol.65 (20), p.9388-9397 |
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| creator | CHEN, Kevin G WANG, Yan C SIKIC, Branimir I SCHANER, Marci E FRANCISCO, Brian DURAN, George E JURIC, Dejan HUFF, Lyn M PADILLA-NASH, Hesed RIED, Thomas FOJO, Tito |
| description | The origin of drug-resistant cells in human cancers has been a fundamental problem of cancer pharmacology. Two major contrasting hypotheses (genetics versus epigenetics) have been proposed to elucidate the mechanisms of acquired drug resistance. In this study, we answer these fundamental questions through investigation of the genetic and epigenetic pathways that control the origin of ABCB1 (MDR1) gene activation with acquired multidrug resistance in drug-sensitive human sarcoma (MES-SA cells). The genetic and epigenetic bases of this selected activation involve the initiation of transcription at a site 112 kb upstream of the ABCB1 proximal promoter (P1) in the drug-resistant cells. This activation was associated with a chromatin-remodeling process characterized by an increase in acetylated histone H3 within a 968-bp region 5' of the ABCB1 upstream promoter. These alterations provide both genetic and epigenetic susceptibility for ABCB1 expression in drug-resistant cells. Complete activation of the ABCB1 gene through the coding region was proposed by interactions of selected trans-alterations or epigenetic changes on the ABCB1 proximal promoter, which occurred during initial drug exposure. Thus, our data provide evidence for a major genomic alteration that changes the chromatin structure of the ABCB1 upstream promoter via acetylation of histone H3 initiating ABCB1 activation, further elucidating the genetic and epigenetic bases that determine chemotherapeutic response in drug-resistant derivatives of MES-SA cells. |
| doi_str_mv | 10.1158/0008-5472.can-04-4133 |
| format | Article |
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Two major contrasting hypotheses (genetics versus epigenetics) have been proposed to elucidate the mechanisms of acquired drug resistance. In this study, we answer these fundamental questions through investigation of the genetic and epigenetic pathways that control the origin of ABCB1 (MDR1) gene activation with acquired multidrug resistance in drug-sensitive human sarcoma (MES-SA cells). The genetic and epigenetic bases of this selected activation involve the initiation of transcription at a site 112 kb upstream of the ABCB1 proximal promoter (P1) in the drug-resistant cells. This activation was associated with a chromatin-remodeling process characterized by an increase in acetylated histone H3 within a 968-bp region 5' of the ABCB1 upstream promoter. These alterations provide both genetic and epigenetic susceptibility for ABCB1 expression in drug-resistant cells. Complete activation of the ABCB1 gene through the coding region was proposed by interactions of selected trans-alterations or epigenetic changes on the ABCB1 proximal promoter, which occurred during initial drug exposure. Thus, our data provide evidence for a major genomic alteration that changes the chromatin structure of the ABCB1 upstream promoter via acetylation of histone H3 initiating ABCB1 activation, further elucidating the genetic and epigenetic bases that determine chemotherapeutic response in drug-resistant derivatives of MES-SA cells.</description><identifier>ISSN: 0008-5472</identifier><identifier>EISSN: 1538-7445</identifier><identifier>DOI: 10.1158/0008-5472.can-04-4133</identifier><identifier>PMID: 16230402</identifier><identifier>CODEN: CNREA8</identifier><language>eng</language><publisher>Philadelphia, PA: American Association for Cancer Research</publisher><subject>Acetylation ; Antineoplastic agents ; Base Sequence ; Biological and medical sciences ; Carrier Proteins - biosynthesis ; Carrier Proteins - genetics ; Cell Line, Tumor ; Chromatin - metabolism ; Doxorubicin - pharmacology ; Drug Resistance, Multiple - genetics ; Drug Resistance, Neoplasm ; Female ; Gene Expression Regulation ; General aspects ; Genes, MDR - genetics ; Histones - metabolism ; Humans ; Intracellular Signaling Peptides and Proteins ; Medical sciences ; Molecular Sequence Data ; Nerve Tissue Proteins - biosynthesis ; Nerve Tissue Proteins - genetics ; Pharmacology. Drug treatments ; Promoter Regions, Genetic ; Reverse Transcriptase Polymerase Chain Reaction ; RNA, Messenger - biosynthesis ; RNA, Messenger - genetics ; Sarcoma - drug therapy ; Sarcoma - genetics ; Sarcoma - metabolism ; Transcriptional Activation ; Uterine Neoplasms - drug therapy ; Uterine Neoplasms - genetics ; Uterine Neoplasms - metabolism</subject><ispartof>Cancer research (Chicago, Ill.), 2005-10, Vol.65 (20), p.9388-9397</ispartof><rights>2006 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c515t-fded8b975922aa71d024642fcf784c7bce0003b5ddf1fdd619de106537178da43</citedby><cites>FETCH-LOGICAL-c515t-fded8b975922aa71d024642fcf784c7bce0003b5ddf1fdd619de106537178da43</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,3356,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=17205434$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16230402$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>CHEN, Kevin G</creatorcontrib><creatorcontrib>WANG, Yan C</creatorcontrib><creatorcontrib>SIKIC, Branimir I</creatorcontrib><creatorcontrib>SCHANER, Marci E</creatorcontrib><creatorcontrib>FRANCISCO, Brian</creatorcontrib><creatorcontrib>DURAN, George E</creatorcontrib><creatorcontrib>JURIC, Dejan</creatorcontrib><creatorcontrib>HUFF, Lyn M</creatorcontrib><creatorcontrib>PADILLA-NASH, Hesed</creatorcontrib><creatorcontrib>RIED, Thomas</creatorcontrib><creatorcontrib>FOJO, Tito</creatorcontrib><title>Genetic and epigenetic modeling of the origins of multidrug-resistant cells in a human sarcoma cell line</title><title>Cancer research (Chicago, Ill.)</title><addtitle>Cancer Res</addtitle><description>The origin of drug-resistant cells in human cancers has been a fundamental problem of cancer pharmacology. Two major contrasting hypotheses (genetics versus epigenetics) have been proposed to elucidate the mechanisms of acquired drug resistance. In this study, we answer these fundamental questions through investigation of the genetic and epigenetic pathways that control the origin of ABCB1 (MDR1) gene activation with acquired multidrug resistance in drug-sensitive human sarcoma (MES-SA cells). The genetic and epigenetic bases of this selected activation involve the initiation of transcription at a site 112 kb upstream of the ABCB1 proximal promoter (P1) in the drug-resistant cells. This activation was associated with a chromatin-remodeling process characterized by an increase in acetylated histone H3 within a 968-bp region 5' of the ABCB1 upstream promoter. These alterations provide both genetic and epigenetic susceptibility for ABCB1 expression in drug-resistant cells. Complete activation of the ABCB1 gene through the coding region was proposed by interactions of selected trans-alterations or epigenetic changes on the ABCB1 proximal promoter, which occurred during initial drug exposure. Thus, our data provide evidence for a major genomic alteration that changes the chromatin structure of the ABCB1 upstream promoter via acetylation of histone H3 initiating ABCB1 activation, further elucidating the genetic and epigenetic bases that determine chemotherapeutic response in drug-resistant derivatives of MES-SA cells.</description><subject>Acetylation</subject><subject>Antineoplastic agents</subject><subject>Base Sequence</subject><subject>Biological and medical sciences</subject><subject>Carrier Proteins - biosynthesis</subject><subject>Carrier Proteins - genetics</subject><subject>Cell Line, Tumor</subject><subject>Chromatin - metabolism</subject><subject>Doxorubicin - pharmacology</subject><subject>Drug Resistance, Multiple - genetics</subject><subject>Drug Resistance, Neoplasm</subject><subject>Female</subject><subject>Gene Expression Regulation</subject><subject>General aspects</subject><subject>Genes, MDR - genetics</subject><subject>Histones - metabolism</subject><subject>Humans</subject><subject>Intracellular Signaling Peptides and Proteins</subject><subject>Medical sciences</subject><subject>Molecular Sequence Data</subject><subject>Nerve Tissue Proteins - biosynthesis</subject><subject>Nerve Tissue Proteins - genetics</subject><subject>Pharmacology. Drug treatments</subject><subject>Promoter Regions, Genetic</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>RNA, Messenger - biosynthesis</subject><subject>RNA, Messenger - genetics</subject><subject>Sarcoma - drug therapy</subject><subject>Sarcoma - genetics</subject><subject>Sarcoma - metabolism</subject><subject>Transcriptional Activation</subject><subject>Uterine Neoplasms - drug therapy</subject><subject>Uterine Neoplasms - genetics</subject><subject>Uterine Neoplasms - metabolism</subject><issn>0008-5472</issn><issn>1538-7445</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkE1PwyAch4nRuDn9CBoueuuEAoUdl0WnyaIXPRPKS4dp6YT24Le3dY07kV94_m8PALcYLTFm4hEhJDJGeb7UKmSIZhQTcgbmmBGRcUrZOZj_MzNwldLXEBlG7BLMcJETRFE-B_utDbbzGqpgoD34aopNa2ztQwVbB7u9hW30lQ9pjE1fd97EvsqiTT51KnRQ27pO0Aeo4L5vVIBJRd026u8DDo3sNbhwqk72ZnoX4PP56WPzku3et6-b9S7TDLMuc8YaUa44W-W5UhwblNOC5k47LqjmpbbDFaRkxjjsjCnwyliMCkY45sIoShbg4dj3ENvv3qZONj6NW6hg2z5JzIngAuEBZEdQxzalaJ08RN-o-CMxkqNiOeqToz65Wb9JROWoeKi7mwb0ZWPNqWpyOgD3E6CSVrWLKmifThzPEaOEkl94CYWF</recordid><startdate>20051015</startdate><enddate>20051015</enddate><creator>CHEN, Kevin G</creator><creator>WANG, Yan C</creator><creator>SIKIC, Branimir I</creator><creator>SCHANER, Marci E</creator><creator>FRANCISCO, Brian</creator><creator>DURAN, George E</creator><creator>JURIC, Dejan</creator><creator>HUFF, Lyn M</creator><creator>PADILLA-NASH, Hesed</creator><creator>RIED, Thomas</creator><creator>FOJO, Tito</creator><general>American Association for Cancer Research</general><scope>IQODW</scope><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>7TM</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope></search><sort><creationdate>20051015</creationdate><title>Genetic and epigenetic modeling of the origins of multidrug-resistant cells in a human sarcoma cell line</title><author>CHEN, Kevin G ; WANG, Yan C ; SIKIC, Branimir I ; SCHANER, Marci E ; FRANCISCO, Brian ; DURAN, George E ; JURIC, Dejan ; HUFF, Lyn M ; PADILLA-NASH, Hesed ; RIED, Thomas ; FOJO, Tito</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c515t-fded8b975922aa71d024642fcf784c7bce0003b5ddf1fdd619de106537178da43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2005</creationdate><topic>Acetylation</topic><topic>Antineoplastic agents</topic><topic>Base Sequence</topic><topic>Biological and medical sciences</topic><topic>Carrier Proteins - biosynthesis</topic><topic>Carrier Proteins - genetics</topic><topic>Cell Line, Tumor</topic><topic>Chromatin - metabolism</topic><topic>Doxorubicin - pharmacology</topic><topic>Drug Resistance, Multiple - genetics</topic><topic>Drug Resistance, Neoplasm</topic><topic>Female</topic><topic>Gene Expression Regulation</topic><topic>General aspects</topic><topic>Genes, MDR - genetics</topic><topic>Histones - metabolism</topic><topic>Humans</topic><topic>Intracellular Signaling Peptides and Proteins</topic><topic>Medical sciences</topic><topic>Molecular Sequence Data</topic><topic>Nerve Tissue Proteins - biosynthesis</topic><topic>Nerve Tissue Proteins - genetics</topic><topic>Pharmacology. Drug treatments</topic><topic>Promoter Regions, Genetic</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><topic>RNA, Messenger - biosynthesis</topic><topic>RNA, Messenger - genetics</topic><topic>Sarcoma - drug therapy</topic><topic>Sarcoma - genetics</topic><topic>Sarcoma - metabolism</topic><topic>Transcriptional Activation</topic><topic>Uterine Neoplasms - drug therapy</topic><topic>Uterine Neoplasms - genetics</topic><topic>Uterine Neoplasms - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>CHEN, Kevin G</creatorcontrib><creatorcontrib>WANG, Yan C</creatorcontrib><creatorcontrib>SIKIC, Branimir I</creatorcontrib><creatorcontrib>SCHANER, Marci E</creatorcontrib><creatorcontrib>FRANCISCO, Brian</creatorcontrib><creatorcontrib>DURAN, George E</creatorcontrib><creatorcontrib>JURIC, Dejan</creatorcontrib><creatorcontrib>HUFF, Lyn M</creatorcontrib><creatorcontrib>PADILLA-NASH, Hesed</creatorcontrib><creatorcontrib>RIED, Thomas</creatorcontrib><creatorcontrib>FOJO, Tito</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Nucleic Acids Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><jtitle>Cancer research (Chicago, Ill.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>CHEN, Kevin G</au><au>WANG, Yan C</au><au>SIKIC, Branimir I</au><au>SCHANER, Marci E</au><au>FRANCISCO, Brian</au><au>DURAN, George E</au><au>JURIC, Dejan</au><au>HUFF, Lyn M</au><au>PADILLA-NASH, Hesed</au><au>RIED, Thomas</au><au>FOJO, Tito</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Genetic and epigenetic modeling of the origins of multidrug-resistant cells in a human sarcoma cell line</atitle><jtitle>Cancer research (Chicago, Ill.)</jtitle><addtitle>Cancer Res</addtitle><date>2005-10-15</date><risdate>2005</risdate><volume>65</volume><issue>20</issue><spage>9388</spage><epage>9397</epage><pages>9388-9397</pages><issn>0008-5472</issn><eissn>1538-7445</eissn><coden>CNREA8</coden><abstract>The origin of drug-resistant cells in human cancers has been a fundamental problem of cancer pharmacology. Two major contrasting hypotheses (genetics versus epigenetics) have been proposed to elucidate the mechanisms of acquired drug resistance. In this study, we answer these fundamental questions through investigation of the genetic and epigenetic pathways that control the origin of ABCB1 (MDR1) gene activation with acquired multidrug resistance in drug-sensitive human sarcoma (MES-SA cells). The genetic and epigenetic bases of this selected activation involve the initiation of transcription at a site 112 kb upstream of the ABCB1 proximal promoter (P1) in the drug-resistant cells. This activation was associated with a chromatin-remodeling process characterized by an increase in acetylated histone H3 within a 968-bp region 5' of the ABCB1 upstream promoter. These alterations provide both genetic and epigenetic susceptibility for ABCB1 expression in drug-resistant cells. Complete activation of the ABCB1 gene through the coding region was proposed by interactions of selected trans-alterations or epigenetic changes on the ABCB1 proximal promoter, which occurred during initial drug exposure. Thus, our data provide evidence for a major genomic alteration that changes the chromatin structure of the ABCB1 upstream promoter via acetylation of histone H3 initiating ABCB1 activation, further elucidating the genetic and epigenetic bases that determine chemotherapeutic response in drug-resistant derivatives of MES-SA cells.</abstract><cop>Philadelphia, PA</cop><pub>American Association for Cancer Research</pub><pmid>16230402</pmid><doi>10.1158/0008-5472.can-04-4133</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Acetylation Antineoplastic agents Base Sequence Biological and medical sciences Carrier Proteins - biosynthesis Carrier Proteins - genetics Cell Line, Tumor Chromatin - metabolism Doxorubicin - pharmacology Drug Resistance, Multiple - genetics Drug Resistance, Neoplasm Female Gene Expression Regulation General aspects Genes, MDR - genetics Histones - metabolism Humans Intracellular Signaling Peptides and Proteins Medical sciences Molecular Sequence Data Nerve Tissue Proteins - biosynthesis Nerve Tissue Proteins - genetics Pharmacology. Drug treatments Promoter Regions, Genetic Reverse Transcriptase Polymerase Chain Reaction RNA, Messenger - biosynthesis RNA, Messenger - genetics Sarcoma - drug therapy Sarcoma - genetics Sarcoma - metabolism Transcriptional Activation Uterine Neoplasms - drug therapy Uterine Neoplasms - genetics Uterine Neoplasms - metabolism |
| title | Genetic and epigenetic modeling of the origins of multidrug-resistant cells in a human sarcoma cell line |
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