Oncogenic HRAS suppresses clusterin expression through promoter hypermethylation
Silencing of gene expression by methylation of CpG islands in regulatory elements is frequently observed in cancer. However, an influence of the most common oncogenic signalling pathways onto DNA methylation has not yet been investigated thoroughly. To address this issue, we identified genes suppres...
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| Veröffentlicht in: | Oncogene 2006-08, Vol.25 (35), p.4890-4903 |
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| creator | Lund, P Weißhaupt, K Mikeska, T Jammas, D Chen, X Kuban, R-J Ungethüm, U Krapfenbauer, U Herzel, H-P Schäfer, R Walter, J Sers, C |
| description | Silencing of gene expression by methylation of CpG islands in regulatory elements is frequently observed in cancer. However, an influence of the most common oncogenic signalling pathways onto DNA methylation has not yet been investigated thoroughly. To address this issue, we identified genes suppressed in
HRAS
-transformed rat fibroblasts but upregulated after treatment with the demethylating agent 5-Aza-2-deoxycytidine and with the MEK1,2 inhibitor U0126. Analysis of gene expression by microarray and Northern blot analysis revealed the MEK/ERK target genes
clusterin
, matrix metalloproteinase 2 (
Mmp2
), peptidylpropyl isomerase C-associated protein
, syndecan 4, Timp2
and
Thbs1
to be repressed in the
HRAS
-transformed FE-8 cells in a MEK/ERK- and methylation-dependent manner. Hypermethylation of putative regulatory elements in
HRAS
-transformed cells as compared to immortalized fibroblasts was detected within a CpG island 14.5 kb upstream of
clusterin
, within the
clusterin
promoter and within a CpG island of the
Mmp2
promoter by bisulphite sequencing. Furthermore, hypermethylation of the
clusterin
promoter was observed 10 days after induction of HRAS in immortalized rat fibroblasts and a clear correlation between reduced
clusterin
expression and hypermethlyation could also be observed in distinct rat tissues. These results suggest that silencing of individual genes by DNA methylation is controlled by oncogenic signalling pathways, yet the mechanisms responsible for initial target gene suppression are variable. |
| doi_str_mv | 10.1038/sj.onc.1209502 |
| format | Article |
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HRAS
-transformed rat fibroblasts but upregulated after treatment with the demethylating agent 5-Aza-2-deoxycytidine and with the MEK1,2 inhibitor U0126. Analysis of gene expression by microarray and Northern blot analysis revealed the MEK/ERK target genes
clusterin
, matrix metalloproteinase 2 (
Mmp2
), peptidylpropyl isomerase C-associated protein
, syndecan 4, Timp2
and
Thbs1
to be repressed in the
HRAS
-transformed FE-8 cells in a MEK/ERK- and methylation-dependent manner. Hypermethylation of putative regulatory elements in
HRAS
-transformed cells as compared to immortalized fibroblasts was detected within a CpG island 14.5 kb upstream of
clusterin
, within the
clusterin
promoter and within a CpG island of the
Mmp2
promoter by bisulphite sequencing. Furthermore, hypermethylation of the
clusterin
promoter was observed 10 days after induction of HRAS in immortalized rat fibroblasts and a clear correlation between reduced
clusterin
expression and hypermethlyation could also be observed in distinct rat tissues. These results suggest that silencing of individual genes by DNA methylation is controlled by oncogenic signalling pathways, yet the mechanisms responsible for initial target gene suppression are variable.</description><identifier>ISSN: 0950-9232</identifier><identifier>EISSN: 1476-5594</identifier><identifier>DOI: 10.1038/sj.onc.1209502</identifier><identifier>PMID: 16568090</identifier><identifier>CODEN: ONCNES</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>Animals ; Antimetabolites, Antineoplastic - pharmacology ; Apoptosis ; Apoptosis - drug effects ; Azacitidine - analogs & derivatives ; Azacitidine - pharmacology ; Biological and medical sciences ; Cell Biology ; Cell Line, Transformed ; Cell physiology ; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes ; Clusterin ; Clusterin - antagonists & inhibitors ; Clusterin - biosynthesis ; Clusterin - genetics ; CpG islands ; DNA Methylation ; DNA microarrays ; Fibroblasts ; Fundamental and applied biological sciences. Psychology ; Gelatinase A ; Gene expression ; Gene silencing ; Genes, ras ; Genes, Suppressor ; Human Genetics ; Hydroxamic Acids - pharmacology ; Internal Medicine ; Matrix metalloproteinase ; Medicine ; Medicine & Public Health ; Metalloproteinase ; Molecular and cellular biology ; Molecular genetics ; Oncology ; original-article ; Promoter Regions, Genetic ; Rats ; Regulatory sequences ; Rodents ; Signal transduction ; Signal Transduction - genetics ; Syndecan ; Tissue inhibitor of metalloproteinase 2 ; Transcription. Transcription factor. Splicing. Rna processing ; Transformed cells</subject><ispartof>Oncogene, 2006-08, Vol.25 (35), p.4890-4903</ispartof><rights>Springer Nature Limited 2006</rights><rights>2006 INIST-CNRS</rights><rights>COPYRIGHT 2006 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Aug 10, 2006</rights><rights>Nature Publishing Group 2006.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c587t-293f468126286c6810b3d35e3c1804a539549c27f15a0a250a5010a22095ab313</citedby><cites>FETCH-LOGICAL-c587t-293f468126286c6810b3d35e3c1804a539549c27f15a0a250a5010a22095ab313</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/sj.onc.1209502$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/sj.onc.1209502$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=18022000$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16568090$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lund, P</creatorcontrib><creatorcontrib>Weißhaupt, K</creatorcontrib><creatorcontrib>Mikeska, T</creatorcontrib><creatorcontrib>Jammas, D</creatorcontrib><creatorcontrib>Chen, X</creatorcontrib><creatorcontrib>Kuban, R-J</creatorcontrib><creatorcontrib>Ungethüm, U</creatorcontrib><creatorcontrib>Krapfenbauer, U</creatorcontrib><creatorcontrib>Herzel, H-P</creatorcontrib><creatorcontrib>Schäfer, R</creatorcontrib><creatorcontrib>Walter, J</creatorcontrib><creatorcontrib>Sers, C</creatorcontrib><title>Oncogenic HRAS suppresses clusterin expression through promoter hypermethylation</title><title>Oncogene</title><addtitle>Oncogene</addtitle><addtitle>Oncogene</addtitle><description>Silencing of gene expression by methylation of CpG islands in regulatory elements is frequently observed in cancer. However, an influence of the most common oncogenic signalling pathways onto DNA methylation has not yet been investigated thoroughly. To address this issue, we identified genes suppressed in
HRAS
-transformed rat fibroblasts but upregulated after treatment with the demethylating agent 5-Aza-2-deoxycytidine and with the MEK1,2 inhibitor U0126. Analysis of gene expression by microarray and Northern blot analysis revealed the MEK/ERK target genes
clusterin
, matrix metalloproteinase 2 (
Mmp2
), peptidylpropyl isomerase C-associated protein
, syndecan 4, Timp2
and
Thbs1
to be repressed in the
HRAS
-transformed FE-8 cells in a MEK/ERK- and methylation-dependent manner. Hypermethylation of putative regulatory elements in
HRAS
-transformed cells as compared to immortalized fibroblasts was detected within a CpG island 14.5 kb upstream of
clusterin
, within the
clusterin
promoter and within a CpG island of the
Mmp2
promoter by bisulphite sequencing. Furthermore, hypermethylation of the
clusterin
promoter was observed 10 days after induction of HRAS in immortalized rat fibroblasts and a clear correlation between reduced
clusterin
expression and hypermethlyation could also be observed in distinct rat tissues. These results suggest that silencing of individual genes by DNA methylation is controlled by oncogenic signalling pathways, yet the mechanisms responsible for initial target gene suppression are variable.</description><subject>Animals</subject><subject>Antimetabolites, Antineoplastic - pharmacology</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Azacitidine - analogs & derivatives</subject><subject>Azacitidine - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Cell Biology</subject><subject>Cell Line, Transformed</subject><subject>Cell physiology</subject><subject>Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes</subject><subject>Clusterin</subject><subject>Clusterin - antagonists & inhibitors</subject><subject>Clusterin - biosynthesis</subject><subject>Clusterin - genetics</subject><subject>CpG islands</subject><subject>DNA Methylation</subject><subject>DNA microarrays</subject><subject>Fibroblasts</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Gelatinase A</subject><subject>Gene expression</subject><subject>Gene silencing</subject><subject>Genes, ras</subject><subject>Genes, Suppressor</subject><subject>Human Genetics</subject><subject>Hydroxamic Acids - pharmacology</subject><subject>Internal Medicine</subject><subject>Matrix metalloproteinase</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Metalloproteinase</subject><subject>Molecular and cellular biology</subject><subject>Molecular genetics</subject><subject>Oncology</subject><subject>original-article</subject><subject>Promoter Regions, Genetic</subject><subject>Rats</subject><subject>Regulatory sequences</subject><subject>Rodents</subject><subject>Signal transduction</subject><subject>Signal Transduction - genetics</subject><subject>Syndecan</subject><subject>Tissue inhibitor of metalloproteinase 2</subject><subject>Transcription. Transcription factor. Splicing. Rna processing</subject><subject>Transformed cells</subject><issn>0950-9232</issn><issn>1476-5594</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNqFkt-L1DAQx4Mo3nr66qMURd-6N0maNnlcDvWEgxN_PIdsNt3N0iY104L735t6hQW5Q_KQYeYz851JhpDXFNYUuLzC4zoGu6YMlAD2hKxo1dSlEKp6Slazr1SMswvyAvEIAI0C9pxc0FrUEhSsyNe7YOPeBW-Lm2-b7wVOw5AcosPCdhOOLvlQuN9_fT6GYjykOO0PxZBiH3O0OJwGl3o3Hk6dGTPxkjxrTYfu1XJfkp-fPv64vilv7z5_ud7cllbIZiyZ4m1VS8pqJmubDdjyHReOWyqhMoIrUSnLmpYKA4YJMAJoNuY5zZZTfkk-3NfNnfyaHI6692hd15ng4oSaUc6ZqOG_IFVNRaGSGXz3D3iMUwp5CM3qinIhRDPrvn2UYg0XqpHNudTedE770MYxGTvr6g2VCoTgdBZcP0Dls3O9tzG41mf_Qwk2RcTkWj0k35t00hT0vA4ajzqvg17WISe8WZqdtr3bnfHl_zPwfgEMWtO1yQTr8cxJyC8OM3d1z2EOhb1L56kfkf4DIWrJ-g</recordid><startdate>20060810</startdate><enddate>20060810</enddate><creator>Lund, P</creator><creator>Weißhaupt, K</creator><creator>Mikeska, T</creator><creator>Jammas, D</creator><creator>Chen, X</creator><creator>Kuban, R-J</creator><creator>Ungethüm, U</creator><creator>Krapfenbauer, U</creator><creator>Herzel, H-P</creator><creator>Schäfer, R</creator><creator>Walter, J</creator><creator>Sers, C</creator><general>Nature Publishing Group UK</general><general>Nature Publishing</general><general>Nature Publishing Group</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>3V.</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M7P</scope><scope>MBDVC</scope><scope>P64</scope><scope>PHGZM</scope><scope>PHGZT</scope><scope>PJZUB</scope><scope>PKEHL</scope><scope>PPXIY</scope><scope>PQEST</scope><scope>PQGLB</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>RC3</scope></search><sort><creationdate>20060810</creationdate><title>Oncogenic HRAS suppresses clusterin expression through promoter hypermethylation</title><author>Lund, P ; Weißhaupt, K ; Mikeska, T ; Jammas, D ; Chen, X ; Kuban, R-J ; Ungethüm, U ; Krapfenbauer, U ; Herzel, H-P ; Schäfer, R ; Walter, J ; Sers, C</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c587t-293f468126286c6810b3d35e3c1804a539549c27f15a0a250a5010a22095ab313</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>Animals</topic><topic>Antimetabolites, Antineoplastic - pharmacology</topic><topic>Apoptosis</topic><topic>Apoptosis - drug effects</topic><topic>Azacitidine - analogs & derivatives</topic><topic>Azacitidine - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Cell Biology</topic><topic>Cell Line, Transformed</topic><topic>Cell physiology</topic><topic>Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes</topic><topic>Clusterin</topic><topic>Clusterin - antagonists & inhibitors</topic><topic>Clusterin - biosynthesis</topic><topic>Clusterin - genetics</topic><topic>CpG islands</topic><topic>DNA Methylation</topic><topic>DNA microarrays</topic><topic>Fibroblasts</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Gelatinase A</topic><topic>Gene expression</topic><topic>Gene silencing</topic><topic>Genes, ras</topic><topic>Genes, Suppressor</topic><topic>Human Genetics</topic><topic>Hydroxamic Acids - pharmacology</topic><topic>Internal Medicine</topic><topic>Matrix metalloproteinase</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Metalloproteinase</topic><topic>Molecular and cellular biology</topic><topic>Molecular genetics</topic><topic>Oncology</topic><topic>original-article</topic><topic>Promoter Regions, Genetic</topic><topic>Rats</topic><topic>Regulatory sequences</topic><topic>Rodents</topic><topic>Signal transduction</topic><topic>Signal Transduction - genetics</topic><topic>Syndecan</topic><topic>Tissue inhibitor of metalloproteinase 2</topic><topic>Transcription. Transcription factor. Splicing. Rna processing</topic><topic>Transformed cells</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lund, P</creatorcontrib><creatorcontrib>Weißhaupt, K</creatorcontrib><creatorcontrib>Mikeska, T</creatorcontrib><creatorcontrib>Jammas, D</creatorcontrib><creatorcontrib>Chen, X</creatorcontrib><creatorcontrib>Kuban, R-J</creatorcontrib><creatorcontrib>Ungethüm, U</creatorcontrib><creatorcontrib>Krapfenbauer, U</creatorcontrib><creatorcontrib>Herzel, H-P</creatorcontrib><creatorcontrib>Schäfer, R</creatorcontrib><creatorcontrib>Walter, J</creatorcontrib><creatorcontrib>Sers, C</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>ProQuest Central (Corporate)</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Research Library</collection><collection>Biological Science Database</collection><collection>Research Library (Corporate)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest Central (New)</collection><collection>ProQuest One Academic (New)</collection><collection>ProQuest Health & Medical Research Collection</collection><collection>ProQuest One Academic Middle East (New)</collection><collection>ProQuest One Health & Nursing</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Applied & Life Sciences</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>Genetics Abstracts</collection><jtitle>Oncogene</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lund, P</au><au>Weißhaupt, K</au><au>Mikeska, T</au><au>Jammas, D</au><au>Chen, X</au><au>Kuban, R-J</au><au>Ungethüm, U</au><au>Krapfenbauer, U</au><au>Herzel, H-P</au><au>Schäfer, R</au><au>Walter, J</au><au>Sers, C</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Oncogenic HRAS suppresses clusterin expression through promoter hypermethylation</atitle><jtitle>Oncogene</jtitle><stitle>Oncogene</stitle><addtitle>Oncogene</addtitle><date>2006-08-10</date><risdate>2006</risdate><volume>25</volume><issue>35</issue><spage>4890</spage><epage>4903</epage><pages>4890-4903</pages><issn>0950-9232</issn><eissn>1476-5594</eissn><coden>ONCNES</coden><abstract>Silencing of gene expression by methylation of CpG islands in regulatory elements is frequently observed in cancer. However, an influence of the most common oncogenic signalling pathways onto DNA methylation has not yet been investigated thoroughly. To address this issue, we identified genes suppressed in
HRAS
-transformed rat fibroblasts but upregulated after treatment with the demethylating agent 5-Aza-2-deoxycytidine and with the MEK1,2 inhibitor U0126. Analysis of gene expression by microarray and Northern blot analysis revealed the MEK/ERK target genes
clusterin
, matrix metalloproteinase 2 (
Mmp2
), peptidylpropyl isomerase C-associated protein
, syndecan 4, Timp2
and
Thbs1
to be repressed in the
HRAS
-transformed FE-8 cells in a MEK/ERK- and methylation-dependent manner. Hypermethylation of putative regulatory elements in
HRAS
-transformed cells as compared to immortalized fibroblasts was detected within a CpG island 14.5 kb upstream of
clusterin
, within the
clusterin
promoter and within a CpG island of the
Mmp2
promoter by bisulphite sequencing. Furthermore, hypermethylation of the
clusterin
promoter was observed 10 days after induction of HRAS in immortalized rat fibroblasts and a clear correlation between reduced
clusterin
expression and hypermethlyation could also be observed in distinct rat tissues. These results suggest that silencing of individual genes by DNA methylation is controlled by oncogenic signalling pathways, yet the mechanisms responsible for initial target gene suppression are variable.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>16568090</pmid><doi>10.1038/sj.onc.1209502</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Springer Nature - Complete Springer Journals; Nature Journals Online; EZB-FREE-00999 freely available EZB journals |
| subjects | Animals Antimetabolites, Antineoplastic - pharmacology Apoptosis Apoptosis - drug effects Azacitidine - analogs & derivatives Azacitidine - pharmacology Biological and medical sciences Cell Biology Cell Line, Transformed Cell physiology Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes Clusterin Clusterin - antagonists & inhibitors Clusterin - biosynthesis Clusterin - genetics CpG islands DNA Methylation DNA microarrays Fibroblasts Fundamental and applied biological sciences. Psychology Gelatinase A Gene expression Gene silencing Genes, ras Genes, Suppressor Human Genetics Hydroxamic Acids - pharmacology Internal Medicine Matrix metalloproteinase Medicine Medicine & Public Health Metalloproteinase Molecular and cellular biology Molecular genetics Oncology original-article Promoter Regions, Genetic Rats Regulatory sequences Rodents Signal transduction Signal Transduction - genetics Syndecan Tissue inhibitor of metalloproteinase 2 Transcription. Transcription factor. Splicing. Rna processing Transformed cells |
| title | Oncogenic HRAS suppresses clusterin expression through promoter hypermethylation |
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