Epigenetic Repression of DNA Mismatch Repair by Inflammation and Hypoxia in Inflammatory Bowel Disease―Associated Colorectal Cancer
Sporadic human mismatch repair (MMR)-deficient colorectal cancers account for approximately 12.5% of all cases of colorectal cancer. MMR-deficient colorectal cancers are classically characterized by right-sided location, multifocality, mucinous histology, and lymphocytic infiltration. However, tumor...
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| Veröffentlicht in: | Cancer research (Chicago, Ill.) Ill.), 2009-08, Vol.69 (16), p.6423-6429 |
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| description | Sporadic human mismatch repair (MMR)-deficient colorectal cancers account for approximately 12.5% of all cases of colorectal cancer. MMR-deficient colorectal cancers are classically characterized by right-sided location, multifocality, mucinous histology, and lymphocytic infiltration. However, tumors in germ-line MMR-deficient mouse models lack these histopathologic features. Mice lacking the heterotrimeric G protein alpha subunit Gialpha2 develop chronic colitis and multifocal, right-sided cancers with mucinous histopathology, similar to human MMR-deficient colorectal cancer. Young Gialpha2-/- colonic epithelium has normal MMR expression but selectively loses MLH1 and consequently PMS2 expression following inflammation. Gialpha2-/- cancers have microsatellite instability. Mlh1 is epigenetically silenced not by promoter hypermethylation but by decreased histone acetylation. Chronically inflamed Gialpha2-/- colonic mucosa contains patchy hypoxia, with increased crypt expression of the hypoxia markers DEC-1 and BNIP3. Chromatin immunoprecipitation identified increased binding of the transcriptional repressor DEC-1 to the proximal Mlh1 promoter in hypoxic YAMC cells and colitic Gialpha2-/- crypts. Treating Gialpha2-/- mice with the histone deacetylase inhibitor suberoylanilide hydroxamic acid significantly decreased colitis activity and rescued MLH1 expression in crypt epithelial cells, which was associated with increased acetyl histone H3 levels and decreased DEC-1 binding at the proximal Mlh1 promoter, consistent with a histone deacetylase-dependent mechanism. These data link chronic hypoxic inflammation, epigenetic MMR protein down-regulation, development of MMR-deficient colorectal cancer, and the firstmouse model of somatically acquired MMR-deficient colorectal cancer. |
| doi_str_mv | 10.1158/0008-5472.CAN-09-1285 |
| format | Article |
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MMR-deficient colorectal cancers are classically characterized by right-sided location, multifocality, mucinous histology, and lymphocytic infiltration. However, tumors in germ-line MMR-deficient mouse models lack these histopathologic features. Mice lacking the heterotrimeric G protein alpha subunit Gialpha2 develop chronic colitis and multifocal, right-sided cancers with mucinous histopathology, similar to human MMR-deficient colorectal cancer. Young Gialpha2-/- colonic epithelium has normal MMR expression but selectively loses MLH1 and consequently PMS2 expression following inflammation. Gialpha2-/- cancers have microsatellite instability. Mlh1 is epigenetically silenced not by promoter hypermethylation but by decreased histone acetylation. Chronically inflamed Gialpha2-/- colonic mucosa contains patchy hypoxia, with increased crypt expression of the hypoxia markers DEC-1 and BNIP3. Chromatin immunoprecipitation identified increased binding of the transcriptional repressor DEC-1 to the proximal Mlh1 promoter in hypoxic YAMC cells and colitic Gialpha2-/- crypts. Treating Gialpha2-/- mice with the histone deacetylase inhibitor suberoylanilide hydroxamic acid significantly decreased colitis activity and rescued MLH1 expression in crypt epithelial cells, which was associated with increased acetyl histone H3 levels and decreased DEC-1 binding at the proximal Mlh1 promoter, consistent with a histone deacetylase-dependent mechanism. These data link chronic hypoxic inflammation, epigenetic MMR protein down-regulation, development of MMR-deficient colorectal cancer, and the firstmouse model of somatically acquired MMR-deficient colorectal cancer.</description><identifier>ISSN: 0008-5472</identifier><identifier>EISSN: 1538-7445</identifier><identifier>DOI: 10.1158/0008-5472.CAN-09-1285</identifier><identifier>PMID: 19638594</identifier><identifier>CODEN: CNREA8</identifier><language>eng</language><publisher>Philadelphia, PA: American Association for Cancer Research</publisher><subject>Adaptor Proteins, Signal Transducing - genetics ; Adaptor Proteins, Signal Transducing - metabolism ; Adenoma - etiology ; Adenoma - genetics ; Adenoma - metabolism ; Adenosine Triphosphatases - genetics ; Adenosine Triphosphatases - metabolism ; Animals ; Antineoplastic agents ; Biological and medical sciences ; Cell Hypoxia - genetics ; Cell Hypoxia - physiology ; Colorectal Neoplasms - etiology ; Colorectal Neoplasms - genetics ; Colorectal Neoplasms - metabolism ; DNA Mismatch Repair - genetics ; DNA Mismatch Repair - physiology ; DNA Repair Enzymes - genetics ; DNA Repair Enzymes - metabolism ; DNA-Binding Proteins - genetics ; DNA-Binding Proteins - metabolism ; Drug Evaluation, Preclinical ; Enzyme Inhibitors - pharmacology ; Epigenesis, Genetic - physiology ; Gastroenterology. Liver. Pancreas. Abdomen ; Gene Expression Regulation, Neoplastic ; Gene Silencing - physiology ; GTP-Binding Protein alpha Subunit, Gi2 - genetics ; Histone Deacetylase Inhibitors ; Hydroxamic Acids - pharmacology ; Inflammation - complications ; Inflammation - genetics ; Inflammation - metabolism ; Inflammatory Bowel Diseases - complications ; Inflammatory Bowel Diseases - genetics ; Inflammatory Bowel Diseases - metabolism ; Intestinal Mucosa - drug effects ; Intestinal Mucosa - metabolism ; Medical sciences ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mismatch Repair Endonuclease PMS2 ; MutL Protein Homolog 1 ; Nuclear Proteins - genetics ; Nuclear Proteins - metabolism ; Other diseases. Semiology ; Pharmacology. Drug treatments ; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus ; Tumors ; Vorinostat</subject><ispartof>Cancer research (Chicago, Ill.), 2009-08, Vol.69 (16), p.6423-6429</ispartof><rights>2009 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c539t-638c975813441db71d79086d28206f547c05a755bccdcf11c132ad4891b2e08e3</citedby><cites>FETCH-LOGICAL-c539t-638c975813441db71d79086d28206f547c05a755bccdcf11c132ad4891b2e08e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,315,782,786,887,3358,27931,27932</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=21959754$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19638594$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>EDWARDS, Robert A</creatorcontrib><creatorcontrib>WITHERSPOON, Mavee</creatorcontrib><creatorcontrib>KEHUI WANG</creatorcontrib><creatorcontrib>AFRASIABI, Kambiz</creatorcontrib><creatorcontrib>PHAM, Trang</creatorcontrib><creatorcontrib>BIRNBAUMER, Lutz</creatorcontrib><creatorcontrib>LIPKIN, Steven M</creatorcontrib><title>Epigenetic Repression of DNA Mismatch Repair by Inflammation and Hypoxia in Inflammatory Bowel Disease―Associated Colorectal Cancer</title><title>Cancer research (Chicago, Ill.)</title><addtitle>Cancer Res</addtitle><description>Sporadic human mismatch repair (MMR)-deficient colorectal cancers account for approximately 12.5% of all cases of colorectal cancer. MMR-deficient colorectal cancers are classically characterized by right-sided location, multifocality, mucinous histology, and lymphocytic infiltration. However, tumors in germ-line MMR-deficient mouse models lack these histopathologic features. Mice lacking the heterotrimeric G protein alpha subunit Gialpha2 develop chronic colitis and multifocal, right-sided cancers with mucinous histopathology, similar to human MMR-deficient colorectal cancer. Young Gialpha2-/- colonic epithelium has normal MMR expression but selectively loses MLH1 and consequently PMS2 expression following inflammation. Gialpha2-/- cancers have microsatellite instability. Mlh1 is epigenetically silenced not by promoter hypermethylation but by decreased histone acetylation. Chronically inflamed Gialpha2-/- colonic mucosa contains patchy hypoxia, with increased crypt expression of the hypoxia markers DEC-1 and BNIP3. Chromatin immunoprecipitation identified increased binding of the transcriptional repressor DEC-1 to the proximal Mlh1 promoter in hypoxic YAMC cells and colitic Gialpha2-/- crypts. Treating Gialpha2-/- mice with the histone deacetylase inhibitor suberoylanilide hydroxamic acid significantly decreased colitis activity and rescued MLH1 expression in crypt epithelial cells, which was associated with increased acetyl histone H3 levels and decreased DEC-1 binding at the proximal Mlh1 promoter, consistent with a histone deacetylase-dependent mechanism. These data link chronic hypoxic inflammation, epigenetic MMR protein down-regulation, development of MMR-deficient colorectal cancer, and the firstmouse model of somatically acquired MMR-deficient colorectal cancer.</description><subject>Adaptor Proteins, Signal Transducing - genetics</subject><subject>Adaptor Proteins, Signal Transducing - metabolism</subject><subject>Adenoma - etiology</subject><subject>Adenoma - genetics</subject><subject>Adenoma - metabolism</subject><subject>Adenosine Triphosphatases - genetics</subject><subject>Adenosine Triphosphatases - metabolism</subject><subject>Animals</subject><subject>Antineoplastic agents</subject><subject>Biological and medical sciences</subject><subject>Cell Hypoxia - genetics</subject><subject>Cell Hypoxia - physiology</subject><subject>Colorectal Neoplasms - etiology</subject><subject>Colorectal Neoplasms - genetics</subject><subject>Colorectal Neoplasms - metabolism</subject><subject>DNA Mismatch Repair - genetics</subject><subject>DNA Mismatch Repair - physiology</subject><subject>DNA Repair Enzymes - genetics</subject><subject>DNA Repair Enzymes - metabolism</subject><subject>DNA-Binding Proteins - genetics</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Drug Evaluation, Preclinical</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Epigenesis, Genetic - physiology</subject><subject>Gastroenterology. Liver. Pancreas. Abdomen</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Gene Silencing - physiology</subject><subject>GTP-Binding Protein alpha Subunit, Gi2 - genetics</subject><subject>Histone Deacetylase Inhibitors</subject><subject>Hydroxamic Acids - pharmacology</subject><subject>Inflammation - complications</subject><subject>Inflammation - genetics</subject><subject>Inflammation - metabolism</subject><subject>Inflammatory Bowel Diseases - complications</subject><subject>Inflammatory Bowel Diseases - genetics</subject><subject>Inflammatory Bowel Diseases - metabolism</subject><subject>Intestinal Mucosa - drug effects</subject><subject>Intestinal Mucosa - metabolism</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Mismatch Repair Endonuclease PMS2</subject><subject>MutL Protein Homolog 1</subject><subject>Nuclear Proteins - genetics</subject><subject>Nuclear Proteins - metabolism</subject><subject>Other diseases. Semiology</subject><subject>Pharmacology. Drug treatments</subject><subject>Stomach. Duodenum. Small intestine. Colon. Rectum. Anus</subject><subject>Tumors</subject><subject>Vorinostat</subject><issn>0008-5472</issn><issn>1538-7445</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkcFu1DAQhi0EokvhEUC-wC3FTuzYviBt05ZWKkVCcLYcZ9IaOXGws8DeuPQR-oJ9Ehx1tYWTZf_f_DOeH6HXlBxRyuV7QogsOBPlUbO-KogqaCn5E7SivJKFYIw_Ras9c4BepPQ9Xzkl_Dk6oKquJFdshW5PJ3cNI8zO4i8wRUjJhRGHHp9crfEnlwYz25tFMi7idosvxt6bIb8umBk7fL6dwm9nsBsftRC3-Dj8Ao9PXAKT4P7P3TqlYJ2ZocNN8CGCnY3HjRktxJfoWW98gle78xB9Ozv92pwXl58_XjTry8LySs1FHtoqwSWtGKNdK2gnFJF1V8qS1H3-qCXcCM5bazvbU2ppVZqOSUXbEoiE6hB9ePCdNu0AnYVxjsbrKbrBxK0Oxun_ldHd6OvwU5eCSclUNni3M4jhxwbSrAeXLHhvRgibpGvBhaS1zCB_AG0MKUXo900o0UuAeglHL-HoHKAmSi8B5ro3_074WLVLLANvd4BJ1vg-5gW6tOdKqnheEav-Aq57pzE</recordid><startdate>20090815</startdate><enddate>20090815</enddate><creator>EDWARDS, Robert A</creator><creator>WITHERSPOON, Mavee</creator><creator>KEHUI WANG</creator><creator>AFRASIABI, Kambiz</creator><creator>PHAM, Trang</creator><creator>BIRNBAUMER, Lutz</creator><creator>LIPKIN, Steven M</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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20090815</creationdate><title>Epigenetic Repression of DNA Mismatch Repair by Inflammation and Hypoxia in Inflammatory Bowel Disease―Associated Colorectal Cancer</title><author>EDWARDS, Robert A ; WITHERSPOON, Mavee ; KEHUI WANG ; AFRASIABI, Kambiz ; PHAM, Trang ; BIRNBAUMER, Lutz ; LIPKIN, Steven M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c539t-638c975813441db71d79086d28206f547c05a755bccdcf11c132ad4891b2e08e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Adaptor Proteins, Signal Transducing - genetics</topic><topic>Adaptor Proteins, Signal Transducing - metabolism</topic><topic>Adenoma - etiology</topic><topic>Adenoma - genetics</topic><topic>Adenoma - metabolism</topic><topic>Adenosine Triphosphatases - genetics</topic><topic>Adenosine Triphosphatases - metabolism</topic><topic>Animals</topic><topic>Antineoplastic agents</topic><topic>Biological and medical sciences</topic><topic>Cell Hypoxia - genetics</topic><topic>Cell Hypoxia - physiology</topic><topic>Colorectal Neoplasms - etiology</topic><topic>Colorectal Neoplasms - genetics</topic><topic>Colorectal Neoplasms - metabolism</topic><topic>DNA Mismatch Repair - genetics</topic><topic>DNA Mismatch Repair - physiology</topic><topic>DNA Repair Enzymes - genetics</topic><topic>DNA Repair Enzymes - metabolism</topic><topic>DNA-Binding Proteins - genetics</topic><topic>DNA-Binding Proteins - metabolism</topic><topic>Drug Evaluation, Preclinical</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Epigenesis, Genetic - physiology</topic><topic>Gastroenterology. Liver. Pancreas. Abdomen</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Gene Silencing - physiology</topic><topic>GTP-Binding Protein alpha Subunit, Gi2 - genetics</topic><topic>Histone Deacetylase Inhibitors</topic><topic>Hydroxamic Acids - pharmacology</topic><topic>Inflammation - complications</topic><topic>Inflammation - genetics</topic><topic>Inflammation - metabolism</topic><topic>Inflammatory Bowel Diseases - complications</topic><topic>Inflammatory Bowel Diseases - genetics</topic><topic>Inflammatory Bowel Diseases - metabolism</topic><topic>Intestinal Mucosa - drug effects</topic><topic>Intestinal Mucosa - metabolism</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Mismatch Repair Endonuclease PMS2</topic><topic>MutL Protein Homolog 1</topic><topic>Nuclear Proteins - genetics</topic><topic>Nuclear Proteins - metabolism</topic><topic>Other diseases. Semiology</topic><topic>Pharmacology. Drug treatments</topic><topic>Stomach. Duodenum. Small intestine. Colon. Rectum. Anus</topic><topic>Tumors</topic><topic>Vorinostat</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>EDWARDS, Robert A</creatorcontrib><creatorcontrib>WITHERSPOON, Mavee</creatorcontrib><creatorcontrib>KEHUI WANG</creatorcontrib><creatorcontrib>AFRASIABI, Kambiz</creatorcontrib><creatorcontrib>PHAM, Trang</creatorcontrib><creatorcontrib>BIRNBAUMER, Lutz</creatorcontrib><creatorcontrib>LIPKIN, Steven M</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>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cancer research (Chicago, Ill.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>EDWARDS, Robert A</au><au>WITHERSPOON, Mavee</au><au>KEHUI WANG</au><au>AFRASIABI, Kambiz</au><au>PHAM, Trang</au><au>BIRNBAUMER, Lutz</au><au>LIPKIN, Steven M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Epigenetic Repression of DNA Mismatch Repair by Inflammation and Hypoxia in Inflammatory Bowel Disease―Associated Colorectal Cancer</atitle><jtitle>Cancer research (Chicago, Ill.)</jtitle><addtitle>Cancer Res</addtitle><date>2009-08-15</date><risdate>2009</risdate><volume>69</volume><issue>16</issue><spage>6423</spage><epage>6429</epage><pages>6423-6429</pages><issn>0008-5472</issn><eissn>1538-7445</eissn><coden>CNREA8</coden><abstract>Sporadic human mismatch repair (MMR)-deficient colorectal cancers account for approximately 12.5% of all cases of colorectal cancer. MMR-deficient colorectal cancers are classically characterized by right-sided location, multifocality, mucinous histology, and lymphocytic infiltration. However, tumors in germ-line MMR-deficient mouse models lack these histopathologic features. Mice lacking the heterotrimeric G protein alpha subunit Gialpha2 develop chronic colitis and multifocal, right-sided cancers with mucinous histopathology, similar to human MMR-deficient colorectal cancer. Young Gialpha2-/- colonic epithelium has normal MMR expression but selectively loses MLH1 and consequently PMS2 expression following inflammation. Gialpha2-/- cancers have microsatellite instability. Mlh1 is epigenetically silenced not by promoter hypermethylation but by decreased histone acetylation. Chronically inflamed Gialpha2-/- colonic mucosa contains patchy hypoxia, with increased crypt expression of the hypoxia markers DEC-1 and BNIP3. Chromatin immunoprecipitation identified increased binding of the transcriptional repressor DEC-1 to the proximal Mlh1 promoter in hypoxic YAMC cells and colitic Gialpha2-/- crypts. Treating Gialpha2-/- mice with the histone deacetylase inhibitor suberoylanilide hydroxamic acid significantly decreased colitis activity and rescued MLH1 expression in crypt epithelial cells, which was associated with increased acetyl histone H3 levels and decreased DEC-1 binding at the proximal Mlh1 promoter, consistent with a histone deacetylase-dependent mechanism. These data link chronic hypoxic inflammation, epigenetic MMR protein down-regulation, development of MMR-deficient colorectal cancer, and the firstmouse model of somatically acquired MMR-deficient colorectal cancer.</abstract><cop>Philadelphia, PA</cop><pub>American Association for Cancer Research</pub><pmid>19638594</pmid><doi>10.1158/0008-5472.CAN-09-1285</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Cancer research (Chicago, Ill.), 2009-08, Vol.69 (16), p.6423-6429 |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; American Association for Cancer Research |
| subjects | Adaptor Proteins, Signal Transducing - genetics Adaptor Proteins, Signal Transducing - metabolism Adenoma - etiology Adenoma - genetics Adenoma - metabolism Adenosine Triphosphatases - genetics Adenosine Triphosphatases - metabolism Animals Antineoplastic agents Biological and medical sciences Cell Hypoxia - genetics Cell Hypoxia - physiology Colorectal Neoplasms - etiology Colorectal Neoplasms - genetics Colorectal Neoplasms - metabolism DNA Mismatch Repair - genetics DNA Mismatch Repair - physiology DNA Repair Enzymes - genetics DNA Repair Enzymes - metabolism DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism Drug Evaluation, Preclinical Enzyme Inhibitors - pharmacology Epigenesis, Genetic - physiology Gastroenterology. Liver. Pancreas. Abdomen Gene Expression Regulation, Neoplastic Gene Silencing - physiology GTP-Binding Protein alpha Subunit, Gi2 - genetics Histone Deacetylase Inhibitors Hydroxamic Acids - pharmacology Inflammation - complications Inflammation - genetics Inflammation - metabolism Inflammatory Bowel Diseases - complications Inflammatory Bowel Diseases - genetics Inflammatory Bowel Diseases - metabolism Intestinal Mucosa - drug effects Intestinal Mucosa - metabolism Medical sciences Mice Mice, Inbred C57BL Mice, Knockout Mismatch Repair Endonuclease PMS2 MutL Protein Homolog 1 Nuclear Proteins - genetics Nuclear Proteins - metabolism Other diseases. Semiology Pharmacology. Drug treatments Stomach. Duodenum. Small intestine. Colon. Rectum. Anus Tumors Vorinostat |
| title | Epigenetic Repression of DNA Mismatch Repair by Inflammation and Hypoxia in Inflammatory Bowel Disease―Associated Colorectal Cancer |
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