Depletion of sirtuin 1 (SIRT1) leads to epigenetic modifications of telomerase (TERT) gene in hepatocellular carcinoma cells
Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD)-dependent deacetylase that is implicated in plethora of biological processes, including metabolism, aging, stress response, and tumorigenesis. Telomerase (TERT) is essential for telomere maintenance. Activation of TERT is considered a cr...
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| description | Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD)-dependent deacetylase that is implicated in plethora of biological processes, including metabolism, aging, stress response, and tumorigenesis. Telomerase (TERT) is essential for telomere maintenance. Activation of TERT is considered a crucial step in tumorigenesis, and therefore it is a potential therapeutic target against cancer. We have recently found that SIRT1 expression is highly elevated in hepatocellular carcinoma, and the depletion of SIRT1 leads to substantial reduction in TERT mRNA and protein expression. However, the underlying molecular mechanism of SIRT1-dependent TERT expression remains uncharacterized. Here, we elucidated if SIRT1 regulates TERT expression via transcriptional, epigenetic and post-transcriptional mechanisms. We report that depletion of SIRT1 does not lead to significant change in transcriptional activity and CpG methylation patterns of the TERT promoter, nor does it affect mRNA stability or 3'-UTR regulation of TERT. Intriguingly, depletion of SIRT1 is associated with substantial induction of acetylated histone H3-K9 and reduction of trimethyl H3-K9 at the TERT gene, which are known to be associated with gene activation. Our data revealed that SIRT1 regulates histone acetylation and methylation at the TERT promoter. We postulated that SIRT1 may regulate TERT expression via long-range interaction, or via yet unidentified histone modifications. |
| doi_str_mv | 10.1371/journal.pone.0084931 |
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Telomerase (TERT) is essential for telomere maintenance. Activation of TERT is considered a crucial step in tumorigenesis, and therefore it is a potential therapeutic target against cancer. We have recently found that SIRT1 expression is highly elevated in hepatocellular carcinoma, and the depletion of SIRT1 leads to substantial reduction in TERT mRNA and protein expression. However, the underlying molecular mechanism of SIRT1-dependent TERT expression remains uncharacterized. Here, we elucidated if SIRT1 regulates TERT expression via transcriptional, epigenetic and post-transcriptional mechanisms. We report that depletion of SIRT1 does not lead to significant change in transcriptional activity and CpG methylation patterns of the TERT promoter, nor does it affect mRNA stability or 3'-UTR regulation of TERT. Intriguingly, depletion of SIRT1 is associated with substantial induction of acetylated histone H3-K9 and reduction of trimethyl H3-K9 at the TERT gene, which are known to be associated with gene activation. Our data revealed that SIRT1 regulates histone acetylation and methylation at the TERT promoter. We postulated that SIRT1 may regulate TERT expression via long-range interaction, or via yet unidentified histone modifications.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0084931</identifier><identifier>PMID: 24416313</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>3' Untranslated regions ; Acetylation ; Activation ; Adenine ; Aging ; Biological activity ; Biology ; Carcinoma, Hepatocellular - pathology ; Cell Line, Tumor ; CpG islands ; Deoxyribonucleic acid ; Depletion ; DNA ; DNA methylation ; Epigenesis, Genetic ; Epigenetics ; Experiments ; Gene expression ; Gene Expression Regulation, Neoplastic - genetics ; Gene Silencing ; Hepatocellular carcinoma ; Histone H3 ; Histones - genetics ; Humans ; Immunoglobulins ; Laboratories ; Liver cancer ; Liver Neoplasms - pathology ; Medicine ; Metabolism ; Methylation ; mRNA stability ; NAD ; Nicotinamide ; Nicotinamide adenine dinucleotide ; Plasmids ; Post-transcription ; Proteins ; Reduction ; Ribosomal DNA ; RNA, Small Interfering - genetics ; SIRT1 protein ; Sirtuin 1 - economics ; Sirtuin 1 - genetics ; Telomerase ; Telomerase - genetics ; Tumorigenesis</subject><ispartof>PloS one, 2014-01, Vol.9 (1), p.e84931-e84931</ispartof><rights>2014 Zhang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2014 Zhang et al 2014 Zhang et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c592t-6b15c7f12b6a8f41b347bc29fcf008e8614181bf1e481e424e98955791ab3f483</citedby><cites>FETCH-LOGICAL-c592t-6b15c7f12b6a8f41b347bc29fcf008e8614181bf1e481e424e98955791ab3f483</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3885646/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3885646/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24416313$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Man, Kwan</contributor><creatorcontrib>Zhang, Bin</creatorcontrib><creatorcontrib>Chen, Juan</creatorcontrib><creatorcontrib>Cheng, Alfred S L</creatorcontrib><creatorcontrib>Ko, Ben C B</creatorcontrib><title>Depletion of sirtuin 1 (SIRT1) leads to epigenetic modifications of telomerase (TERT) gene in hepatocellular carcinoma cells</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD)-dependent deacetylase that is implicated in plethora of biological processes, including metabolism, aging, stress response, and tumorigenesis. Telomerase (TERT) is essential for telomere maintenance. Activation of TERT is considered a crucial step in tumorigenesis, and therefore it is a potential therapeutic target against cancer. We have recently found that SIRT1 expression is highly elevated in hepatocellular carcinoma, and the depletion of SIRT1 leads to substantial reduction in TERT mRNA and protein expression. However, the underlying molecular mechanism of SIRT1-dependent TERT expression remains uncharacterized. Here, we elucidated if SIRT1 regulates TERT expression via transcriptional, epigenetic and post-transcriptional mechanisms. We report that depletion of SIRT1 does not lead to significant change in transcriptional activity and CpG methylation patterns of the TERT promoter, nor does it affect mRNA stability or 3'-UTR regulation of TERT. Intriguingly, depletion of SIRT1 is associated with substantial induction of acetylated histone H3-K9 and reduction of trimethyl H3-K9 at the TERT gene, which are known to be associated with gene activation. Our data revealed that SIRT1 regulates histone acetylation and methylation at the TERT promoter. We postulated that SIRT1 may regulate TERT expression via long-range interaction, or via yet unidentified histone modifications.</description><subject>3' Untranslated regions</subject><subject>Acetylation</subject><subject>Activation</subject><subject>Adenine</subject><subject>Aging</subject><subject>Biological activity</subject><subject>Biology</subject><subject>Carcinoma, Hepatocellular - pathology</subject><subject>Cell Line, Tumor</subject><subject>CpG islands</subject><subject>Deoxyribonucleic acid</subject><subject>Depletion</subject><subject>DNA</subject><subject>DNA methylation</subject><subject>Epigenesis, Genetic</subject><subject>Epigenetics</subject><subject>Experiments</subject><subject>Gene expression</subject><subject>Gene Expression Regulation, Neoplastic - genetics</subject><subject>Gene Silencing</subject><subject>Hepatocellular carcinoma</subject><subject>Histone H3</subject><subject>Histones - genetics</subject><subject>Humans</subject><subject>Immunoglobulins</subject><subject>Laboratories</subject><subject>Liver cancer</subject><subject>Liver Neoplasms - pathology</subject><subject>Medicine</subject><subject>Metabolism</subject><subject>Methylation</subject><subject>mRNA stability</subject><subject>NAD</subject><subject>Nicotinamide</subject><subject>Nicotinamide adenine dinucleotide</subject><subject>Plasmids</subject><subject>Post-transcription</subject><subject>Proteins</subject><subject>Reduction</subject><subject>Ribosomal DNA</subject><subject>RNA, Small Interfering - genetics</subject><subject>SIRT1 protein</subject><subject>Sirtuin 1 - economics</subject><subject>Sirtuin 1 - genetics</subject><subject>Telomerase</subject><subject>Telomerase - genetics</subject><subject>Tumorigenesis</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNptUtFqFDEUHUSxdfUPRAO-bB92nTvJZDIvgrRVFwpCXZ9DJnuzzZKZjMmMIPjxzXSnpRUfQsLNOeeec7lZ9hbyNdAKPh78GDrl1r3vcJ3ngtUUnmWnUNNixYucPn_0PslexXjI85IKzl9mJwVjwCnQ0-zvBfYOB-s74g2JNgyj7QiQ5Y_N9RbOiEO1i2TwBHu7xy4hNWn9zhqr1cSKE21A51sMKiJZbi-vt2dkgpIkdIO9GrxG50anAtEqaNv5VpGpFF9nL4xyEd_M9yL7-eVye_5tdfX96-b889VKl3UxrHgDpa4MFA1XwjBoKKsaXdRGm5QbBQcGAhoDyEQ6BcNa1GVZ1aAaapigi-z9Ubd3Psp5cFECqziINJUqITZHxM6rg-yDbVX4I72y8q7gw16qkLI7lCq1VawxBrVhtDCCVhUmI8lPY-pkbpF9mruNTYs7jd0QlHsi-vSnszdy739LKkTJGU8Cy1kg-F8jxkG2Nk4DUx36cfJd5xVn5V2yD_9A_5-OHVE6-BgDmgczkMtpme5ZclomOS9Tor17HOSBdL899BabW8jI</recordid><startdate>20140108</startdate><enddate>20140108</enddate><creator>Zhang, Bin</creator><creator>Chen, Juan</creator><creator>Cheng, Alfred S L</creator><creator>Ko, Ben C B</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><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>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20140108</creationdate><title>Depletion of sirtuin 1 (SIRT1) leads to epigenetic modifications of telomerase (TERT) gene in hepatocellular carcinoma cells</title><author>Zhang, Bin ; Chen, Juan ; Cheng, Alfred S L ; Ko, Ben C B</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c592t-6b15c7f12b6a8f41b347bc29fcf008e8614181bf1e481e424e98955791ab3f483</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>3' Untranslated regions</topic><topic>Acetylation</topic><topic>Activation</topic><topic>Adenine</topic><topic>Aging</topic><topic>Biological activity</topic><topic>Biology</topic><topic>Carcinoma, Hepatocellular - pathology</topic><topic>Cell Line, Tumor</topic><topic>CpG islands</topic><topic>Deoxyribonucleic acid</topic><topic>Depletion</topic><topic>DNA</topic><topic>DNA methylation</topic><topic>Epigenesis, Genetic</topic><topic>Epigenetics</topic><topic>Experiments</topic><topic>Gene expression</topic><topic>Gene Expression Regulation, Neoplastic - genetics</topic><topic>Gene Silencing</topic><topic>Hepatocellular carcinoma</topic><topic>Histone H3</topic><topic>Histones - genetics</topic><topic>Humans</topic><topic>Immunoglobulins</topic><topic>Laboratories</topic><topic>Liver cancer</topic><topic>Liver Neoplasms - pathology</topic><topic>Medicine</topic><topic>Metabolism</topic><topic>Methylation</topic><topic>mRNA stability</topic><topic>NAD</topic><topic>Nicotinamide</topic><topic>Nicotinamide adenine dinucleotide</topic><topic>Plasmids</topic><topic>Post-transcription</topic><topic>Proteins</topic><topic>Reduction</topic><topic>Ribosomal DNA</topic><topic>RNA, Small Interfering - genetics</topic><topic>SIRT1 protein</topic><topic>Sirtuin 1 - economics</topic><topic>Sirtuin 1 - genetics</topic><topic>Telomerase</topic><topic>Telomerase - genetics</topic><topic>Tumorigenesis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhang, Bin</creatorcontrib><creatorcontrib>Chen, Juan</creatorcontrib><creatorcontrib>Cheng, Alfred S L</creatorcontrib><creatorcontrib>Ko, Ben C B</creatorcontrib><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>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</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 Technology 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>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</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>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhang, Bin</au><au>Chen, Juan</au><au>Cheng, Alfred S L</au><au>Ko, Ben C B</au><au>Man, Kwan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Depletion of sirtuin 1 (SIRT1) leads to epigenetic modifications of telomerase (TERT) gene in hepatocellular carcinoma cells</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2014-01-08</date><risdate>2014</risdate><volume>9</volume><issue>1</issue><spage>e84931</spage><epage>e84931</epage><pages>e84931-e84931</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD)-dependent deacetylase that is implicated in plethora of biological processes, including metabolism, aging, stress response, and tumorigenesis. Telomerase (TERT) is essential for telomere maintenance. Activation of TERT is considered a crucial step in tumorigenesis, and therefore it is a potential therapeutic target against cancer. We have recently found that SIRT1 expression is highly elevated in hepatocellular carcinoma, and the depletion of SIRT1 leads to substantial reduction in TERT mRNA and protein expression. However, the underlying molecular mechanism of SIRT1-dependent TERT expression remains uncharacterized. Here, we elucidated if SIRT1 regulates TERT expression via transcriptional, epigenetic and post-transcriptional mechanisms. We report that depletion of SIRT1 does not lead to significant change in transcriptional activity and CpG methylation patterns of the TERT promoter, nor does it affect mRNA stability or 3'-UTR regulation of TERT. Intriguingly, depletion of SIRT1 is associated with substantial induction of acetylated histone H3-K9 and reduction of trimethyl H3-K9 at the TERT gene, which are known to be associated with gene activation. Our data revealed that SIRT1 regulates histone acetylation and methylation at the TERT promoter. We postulated that SIRT1 may regulate TERT expression via long-range interaction, or via yet unidentified histone modifications.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24416313</pmid><doi>10.1371/journal.pone.0084931</doi><oa>free_for_read</oa></addata></record> |
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| subjects | 3' Untranslated regions Acetylation Activation Adenine Aging Biological activity Biology Carcinoma, Hepatocellular - pathology Cell Line, Tumor CpG islands Deoxyribonucleic acid Depletion DNA DNA methylation Epigenesis, Genetic Epigenetics Experiments Gene expression Gene Expression Regulation, Neoplastic - genetics Gene Silencing Hepatocellular carcinoma Histone H3 Histones - genetics Humans Immunoglobulins Laboratories Liver cancer Liver Neoplasms - pathology Medicine Metabolism Methylation mRNA stability NAD Nicotinamide Nicotinamide adenine dinucleotide Plasmids Post-transcription Proteins Reduction Ribosomal DNA RNA, Small Interfering - genetics SIRT1 protein Sirtuin 1 - economics Sirtuin 1 - genetics Telomerase Telomerase - genetics Tumorigenesis |
| title | Depletion of sirtuin 1 (SIRT1) leads to epigenetic modifications of telomerase (TERT) gene in hepatocellular carcinoma cells |
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