Inhibiting histone deacetylases suppresses glucose metabolism and hepatocellular carcinoma growth by restoring FBP1 expression
Hepatocellular carcinoma (HCC) is one of the most commonly diagnosed cancers in the world. Elevated glucose metabolism in the availability of oxygen, a phenomenon called the Warburg effect, is important for cancer cell growth. Fructose-1,6-bisphosphatase (FBP1) is a rate-limiting enzyme in gluconeog...
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| description | Hepatocellular carcinoma (HCC) is one of the most commonly diagnosed cancers in the world. Elevated glucose metabolism in the availability of oxygen, a phenomenon called the Warburg effect, is important for cancer cell growth. Fructose-1,6-bisphosphatase (FBP1) is a rate-limiting enzyme in gluconeogenesis and is frequently lost in various types of cancer. Here, we demonstrated that expression of FBP1 was downregulated in HCC patient specimens and decreased expression of FBP1 associated with poor prognosis. Low expression of FBP1 correlated with high levels of histone deacetylase 1 (HDAC1) and HDAC2 proteins in HCC patient tissues. Treatment of HCC cells with HDAC inhibitors or knockdown of HDAC1 and/or HDAC2 restored FBP1 expression and inhibited HCC cell growth. HDAC-mediated suppression of FBP1 expression correlated with decreased histone H3 lysine 27 acetylation (H3K27Ac) in the
FBP1
enhancer. Restored expression of FBP1 decreased glucose reduction and lactate secretion and inhibited HCC cell growth
in vitro
and tumor growth in mice. Our data reveal that loss of FBP1 due to histone deacetylation associates with poor prognosis of HCC and restored FBP1 expression by HDAC inhibitors suppresses HCC growth. Our findings suggest that repression of FBP1 by HDACs has important implications for HCC prognosis and treatment. |
| doi_str_mv | 10.1038/srep43864 |
| format | Article |
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FBP1
enhancer. Restored expression of FBP1 decreased glucose reduction and lactate secretion and inhibited HCC cell growth
in vitro
and tumor growth in mice. Our data reveal that loss of FBP1 due to histone deacetylation associates with poor prognosis of HCC and restored FBP1 expression by HDAC inhibitors suppresses HCC growth. Our findings suggest that repression of FBP1 by HDACs has important implications for HCC prognosis and treatment.</description><identifier>ISSN: 2045-2322</identifier><identifier>EISSN: 2045-2322</identifier><identifier>DOI: 10.1038/srep43864</identifier><identifier>PMID: 28262837</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13 ; 13/105 ; 13/109 ; 14 ; 38 ; 38/77 ; 38/79 ; 42 ; 45 ; 45/15 ; 631/337 ; 631/67/2327 ; Acetylation ; Animals ; Carcinoma, Hepatocellular - genetics ; Carcinoma, Hepatocellular - metabolism ; Carcinoma, Hepatocellular - prevention & control ; Cell growth ; Cell Line, Tumor ; Deacetylation ; Female ; Fructose ; Fructose-Bisphosphatase - genetics ; Fructose-Bisphosphatase - metabolism ; Gene Expression Regulation, Neoplastic - drug effects ; Gluconeogenesis ; Glucose ; Glucose - metabolism ; HDAC2 protein ; Hep G2 Cells ; Hepatocellular carcinoma ; Histone deacetylase ; Histone Deacetylase Inhibitors - pharmacology ; Histone Deacetylases - genetics ; Histone Deacetylases - metabolism ; Histone H3 ; Humanities and Social Sciences ; Humans ; Kaplan-Meier Estimate ; Lactic acid ; Liver cancer ; Liver Neoplasms - genetics ; Liver Neoplasms - metabolism ; Liver Neoplasms - prevention & control ; Lysine ; Male ; Metabolism ; Mice, Inbred NOD ; Mice, Knockout ; Mice, SCID ; Middle Aged ; multidisciplinary ; Prognosis ; RNA Interference ; Rodents ; Science ; Secretion ; Tumor Burden - drug effects ; Tumor Burden - genetics ; Xenograft Model Antitumor Assays</subject><ispartof>Scientific reports, 2017-03, Vol.7 (1), p.43864-43864, Article 43864</ispartof><rights>The Author(s) 2017</rights><rights>Copyright Nature Publishing Group Mar 2017</rights><rights>Copyright © 2017, The Author(s) 2017 The Author(s)</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c504t-261613d8e3a52548700d42a8f1fe6a324efb23db2242a9fefc9e5cad0410ede63</citedby><cites>FETCH-LOGICAL-c504t-261613d8e3a52548700d42a8f1fe6a324efb23db2242a9fefc9e5cad0410ede63</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/PMC5338333/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5338333/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,27924,27925,41120,42189,51576,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28262837$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yang, Jing</creatorcontrib><creatorcontrib>Jin, Xin</creatorcontrib><creatorcontrib>Yan, Yuqian</creatorcontrib><creatorcontrib>Shao, Yingjie</creatorcontrib><creatorcontrib>Pan, Yunqian</creatorcontrib><creatorcontrib>Roberts, Lewis R.</creatorcontrib><creatorcontrib>Zhang, Jun</creatorcontrib><creatorcontrib>Huang, Haojie</creatorcontrib><creatorcontrib>Jiang, Jingting</creatorcontrib><title>Inhibiting histone deacetylases suppresses glucose metabolism and hepatocellular carcinoma growth by restoring FBP1 expression</title><title>Scientific reports</title><addtitle>Sci Rep</addtitle><addtitle>Sci Rep</addtitle><description>Hepatocellular carcinoma (HCC) is one of the most commonly diagnosed cancers in the world. Elevated glucose metabolism in the availability of oxygen, a phenomenon called the Warburg effect, is important for cancer cell growth. Fructose-1,6-bisphosphatase (FBP1) is a rate-limiting enzyme in gluconeogenesis and is frequently lost in various types of cancer. Here, we demonstrated that expression of FBP1 was downregulated in HCC patient specimens and decreased expression of FBP1 associated with poor prognosis. Low expression of FBP1 correlated with high levels of histone deacetylase 1 (HDAC1) and HDAC2 proteins in HCC patient tissues. Treatment of HCC cells with HDAC inhibitors or knockdown of HDAC1 and/or HDAC2 restored FBP1 expression and inhibited HCC cell growth. HDAC-mediated suppression of FBP1 expression correlated with decreased histone H3 lysine 27 acetylation (H3K27Ac) in the
FBP1
enhancer. Restored expression of FBP1 decreased glucose reduction and lactate secretion and inhibited HCC cell growth
in vitro
and tumor growth in mice. Our data reveal that loss of FBP1 due to histone deacetylation associates with poor prognosis of HCC and restored FBP1 expression by HDAC inhibitors suppresses HCC growth. Our findings suggest that repression of FBP1 by HDACs has important implications for HCC prognosis and treatment.</description><subject>13</subject><subject>13/105</subject><subject>13/109</subject><subject>14</subject><subject>38</subject><subject>38/77</subject><subject>38/79</subject><subject>42</subject><subject>45</subject><subject>45/15</subject><subject>631/337</subject><subject>631/67/2327</subject><subject>Acetylation</subject><subject>Animals</subject><subject>Carcinoma, Hepatocellular - genetics</subject><subject>Carcinoma, Hepatocellular - metabolism</subject><subject>Carcinoma, Hepatocellular - prevention & control</subject><subject>Cell growth</subject><subject>Cell Line, Tumor</subject><subject>Deacetylation</subject><subject>Female</subject><subject>Fructose</subject><subject>Fructose-Bisphosphatase - genetics</subject><subject>Fructose-Bisphosphatase - metabolism</subject><subject>Gene Expression Regulation, Neoplastic - drug effects</subject><subject>Gluconeogenesis</subject><subject>Glucose</subject><subject>Glucose - metabolism</subject><subject>HDAC2 protein</subject><subject>Hep G2 Cells</subject><subject>Hepatocellular carcinoma</subject><subject>Histone deacetylase</subject><subject>Histone Deacetylase Inhibitors - pharmacology</subject><subject>Histone Deacetylases - genetics</subject><subject>Histone Deacetylases - metabolism</subject><subject>Histone H3</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>Kaplan-Meier Estimate</subject><subject>Lactic acid</subject><subject>Liver cancer</subject><subject>Liver Neoplasms - genetics</subject><subject>Liver Neoplasms - metabolism</subject><subject>Liver Neoplasms - prevention & control</subject><subject>Lysine</subject><subject>Male</subject><subject>Metabolism</subject><subject>Mice, Inbred NOD</subject><subject>Mice, Knockout</subject><subject>Mice, SCID</subject><subject>Middle Aged</subject><subject>multidisciplinary</subject><subject>Prognosis</subject><subject>RNA Interference</subject><subject>Rodents</subject><subject>Science</subject><subject>Secretion</subject><subject>Tumor Burden - drug effects</subject><subject>Tumor Burden - genetics</subject><subject>Xenograft Model Antitumor Assays</subject><issn>2045-2322</issn><issn>2045-2322</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNplkU9v1DAQxa0K1FZLD3yBylIvgLTU_5I4FySoKFSqRA9wthxnsnGV2KntAHvhs-OwZbWFuXhk__TmjR9CLyl5SwmXlzHAJLgsxRE6ZUQUa8YZe3bQn6CzGO9JroLVgtbH6IRJVjLJq1P068b1trHJug3ubUzeAW5BG0jbQUeIOM7TFCAu7WaYjY-AR0i68YONI9auxT1MOnkDwzAPOmCjg7HOjxpvgv-RetxscRZIPiwzrj_cUQw__0ha716g550eIpw9niv07frj16vP69svn26u3t-uTUFEWrOSlpS3ErguWCFkRUgrmJYd7aDUnAnoGsbbhrF8W3fQmRoKo1siKIEWSr5C73a609yM0BpwKehBTcGOOmyV11Y9fXG2Vxv_XRWcS55rhV49CgT_MOd11GjjsrN24OeoqKxEJSspSEYv_kHv_RxcXk_RmnBeZpOLo9c7ygQfc4bd3gwlaglW7YPN7Pmh-z35N8YMvNkBcVp-GcLByP_UfgObwrCz</recordid><startdate>20170306</startdate><enddate>20170306</enddate><creator>Yang, Jing</creator><creator>Jin, Xin</creator><creator>Yan, Yuqian</creator><creator>Shao, Yingjie</creator><creator>Pan, Yunqian</creator><creator>Roberts, Lewis R.</creator><creator>Zhang, Jun</creator><creator>Huang, Haojie</creator><creator>Jiang, Jingting</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>C6C</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>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>88I</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2P</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20170306</creationdate><title>Inhibiting histone deacetylases suppresses glucose metabolism and hepatocellular carcinoma growth by restoring FBP1 expression</title><author>Yang, Jing ; Jin, Xin ; Yan, Yuqian ; Shao, Yingjie ; Pan, Yunqian ; Roberts, Lewis R. ; Zhang, Jun ; Huang, Haojie ; Jiang, Jingting</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c504t-261613d8e3a52548700d42a8f1fe6a324efb23db2242a9fefc9e5cad0410ede63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>13</topic><topic>13/105</topic><topic>13/109</topic><topic>14</topic><topic>38</topic><topic>38/77</topic><topic>38/79</topic><topic>42</topic><topic>45</topic><topic>45/15</topic><topic>631/337</topic><topic>631/67/2327</topic><topic>Acetylation</topic><topic>Animals</topic><topic>Carcinoma, Hepatocellular - genetics</topic><topic>Carcinoma, Hepatocellular - metabolism</topic><topic>Carcinoma, Hepatocellular - prevention & control</topic><topic>Cell growth</topic><topic>Cell Line, Tumor</topic><topic>Deacetylation</topic><topic>Female</topic><topic>Fructose</topic><topic>Fructose-Bisphosphatase - genetics</topic><topic>Fructose-Bisphosphatase - metabolism</topic><topic>Gene Expression Regulation, Neoplastic - drug effects</topic><topic>Gluconeogenesis</topic><topic>Glucose</topic><topic>Glucose - metabolism</topic><topic>HDAC2 protein</topic><topic>Hep G2 Cells</topic><topic>Hepatocellular carcinoma</topic><topic>Histone deacetylase</topic><topic>Histone Deacetylase Inhibitors - pharmacology</topic><topic>Histone Deacetylases - genetics</topic><topic>Histone Deacetylases - metabolism</topic><topic>Histone H3</topic><topic>Humanities and Social Sciences</topic><topic>Humans</topic><topic>Kaplan-Meier Estimate</topic><topic>Lactic acid</topic><topic>Liver cancer</topic><topic>Liver Neoplasms - genetics</topic><topic>Liver Neoplasms - metabolism</topic><topic>Liver Neoplasms - prevention & control</topic><topic>Lysine</topic><topic>Male</topic><topic>Metabolism</topic><topic>Mice, Inbred NOD</topic><topic>Mice, Knockout</topic><topic>Mice, SCID</topic><topic>Middle Aged</topic><topic>multidisciplinary</topic><topic>Prognosis</topic><topic>RNA Interference</topic><topic>Rodents</topic><topic>Science</topic><topic>Secretion</topic><topic>Tumor Burden - drug effects</topic><topic>Tumor Burden - genetics</topic><topic>Xenograft Model Antitumor Assays</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yang, Jing</creatorcontrib><creatorcontrib>Jin, Xin</creatorcontrib><creatorcontrib>Yan, Yuqian</creatorcontrib><creatorcontrib>Shao, Yingjie</creatorcontrib><creatorcontrib>Pan, Yunqian</creatorcontrib><creatorcontrib>Roberts, Lewis R.</creatorcontrib><creatorcontrib>Zhang, Jun</creatorcontrib><creatorcontrib>Huang, Haojie</creatorcontrib><creatorcontrib>Jiang, Jingting</creatorcontrib><collection>Springer Nature OA Free Journals</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>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>Science Database (Alumni Edition)</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>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</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>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</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>Science Database</collection><collection>Biological Science Database</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Scientific reports</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yang, Jing</au><au>Jin, Xin</au><au>Yan, Yuqian</au><au>Shao, Yingjie</au><au>Pan, Yunqian</au><au>Roberts, Lewis R.</au><au>Zhang, Jun</au><au>Huang, Haojie</au><au>Jiang, Jingting</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhibiting histone deacetylases suppresses glucose metabolism and hepatocellular carcinoma growth by restoring FBP1 expression</atitle><jtitle>Scientific reports</jtitle><stitle>Sci Rep</stitle><addtitle>Sci Rep</addtitle><date>2017-03-06</date><risdate>2017</risdate><volume>7</volume><issue>1</issue><spage>43864</spage><epage>43864</epage><pages>43864-43864</pages><artnum>43864</artnum><issn>2045-2322</issn><eissn>2045-2322</eissn><abstract>Hepatocellular carcinoma (HCC) is one of the most commonly diagnosed cancers in the world. Elevated glucose metabolism in the availability of oxygen, a phenomenon called the Warburg effect, is important for cancer cell growth. Fructose-1,6-bisphosphatase (FBP1) is a rate-limiting enzyme in gluconeogenesis and is frequently lost in various types of cancer. Here, we demonstrated that expression of FBP1 was downregulated in HCC patient specimens and decreased expression of FBP1 associated with poor prognosis. Low expression of FBP1 correlated with high levels of histone deacetylase 1 (HDAC1) and HDAC2 proteins in HCC patient tissues. Treatment of HCC cells with HDAC inhibitors or knockdown of HDAC1 and/or HDAC2 restored FBP1 expression and inhibited HCC cell growth. HDAC-mediated suppression of FBP1 expression correlated with decreased histone H3 lysine 27 acetylation (H3K27Ac) in the
FBP1
enhancer. Restored expression of FBP1 decreased glucose reduction and lactate secretion and inhibited HCC cell growth
in vitro
and tumor growth in mice. Our data reveal that loss of FBP1 due to histone deacetylation associates with poor prognosis of HCC and restored FBP1 expression by HDAC inhibitors suppresses HCC growth. Our findings suggest that repression of FBP1 by HDACs has important implications for HCC prognosis and treatment.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>28262837</pmid><doi>10.1038/srep43864</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 13 13/105 13/109 14 38 38/77 38/79 42 45 45/15 631/337 631/67/2327 Acetylation Animals Carcinoma, Hepatocellular - genetics Carcinoma, Hepatocellular - metabolism Carcinoma, Hepatocellular - prevention & control Cell growth Cell Line, Tumor Deacetylation Female Fructose Fructose-Bisphosphatase - genetics Fructose-Bisphosphatase - metabolism Gene Expression Regulation, Neoplastic - drug effects Gluconeogenesis Glucose Glucose - metabolism HDAC2 protein Hep G2 Cells Hepatocellular carcinoma Histone deacetylase Histone Deacetylase Inhibitors - pharmacology Histone Deacetylases - genetics Histone Deacetylases - metabolism Histone H3 Humanities and Social Sciences Humans Kaplan-Meier Estimate Lactic acid Liver cancer Liver Neoplasms - genetics Liver Neoplasms - metabolism Liver Neoplasms - prevention & control Lysine Male Metabolism Mice, Inbred NOD Mice, Knockout Mice, SCID Middle Aged multidisciplinary Prognosis RNA Interference Rodents Science Secretion Tumor Burden - drug effects Tumor Burden - genetics Xenograft Model Antitumor Assays |
| title | Inhibiting histone deacetylases suppresses glucose metabolism and hepatocellular carcinoma growth by restoring FBP1 expression |
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