The Histone H3 Methyltransferase G9A Epigenetically Activates the Serine-Glycine Synthesis Pathway to Sustain Cancer Cell Survival and Proliferation
Increased activation of the serine-glycine biosynthetic pathway is an integral part of cancer metabolism that drives macromolecule synthesis needed for cell proliferation. Whether this pathway is under epigenetic control is unknown. Here we show that the histone H3 lysine 9 (H3K9) methyltransferase...
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| Veröffentlicht in: | Cell metabolism 2013-12, Vol.18 (6), p.896-907 |
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| creator | Ding, Jane Li, Tai Wang, Xiangwei Zhao, Erhu Choi, Jeong-Hyeon Yang, Liqun Zha, Yunhong Dong, Zheng Huang, Shuang Asara, John M. Cui, Hongjuan Ding, Han-Fei |
| description | Increased activation of the serine-glycine biosynthetic pathway is an integral part of cancer metabolism that drives macromolecule synthesis needed for cell proliferation. Whether this pathway is under epigenetic control is unknown. Here we show that the histone H3 lysine 9 (H3K9) methyltransferase G9A is required for maintaining the pathway enzyme genes in an active state marked by H3K9 monomethylation and for the transcriptional activation of this pathway in response to serine deprivation. G9A inactivation depletes serine and its downstream metabolites, triggering cell death with autophagy in cancer cell lines of different tissue origins. Higher G9A expression, which is observed in various cancers and is associated with greater mortality in cancer patients, increases serine production and enhances the proliferation and tumorigenicity of cancer cells. These findings identify a G9A-dependent epigenetic program in the control of cancer metabolism, providing a rationale for G9A inhibition as a therapeutic strategy for cancer.
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•G9A sustains cancer cell survival and proliferation•G9A epigenetically activates the serine-glycine biosynthetic pathway•G9A links serine sensing to ribosome biogenesis and cell-cycle progression•G9A has an oncogenic function in tumorigenesis |
| doi_str_mv | 10.1016/j.cmet.2013.11.004 |
| format | Article |
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•G9A sustains cancer cell survival and proliferation•G9A epigenetically activates the serine-glycine biosynthetic pathway•G9A links serine sensing to ribosome biogenesis and cell-cycle progression•G9A has an oncogenic function in tumorigenesis</description><identifier>ISSN: 1550-4131</identifier><identifier>EISSN: 1932-7420</identifier><identifier>DOI: 10.1016/j.cmet.2013.11.004</identifier><identifier>PMID: 24315373</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Autophagy - drug effects ; Azepines - pharmacology ; Bone Neoplasms - metabolism ; Bone Neoplasms - pathology ; Cell Line, Tumor ; Cell Proliferation ; Cell Survival - drug effects ; Epigenomics ; Glycine - biosynthesis ; HeLa Cells ; Histocompatibility Antigens - genetics ; Histocompatibility Antigens - metabolism ; Histone-Lysine N-Methyltransferase - antagonists & inhibitors ; Histone-Lysine N-Methyltransferase - genetics ; Histone-Lysine N-Methyltransferase - metabolism ; Histones - metabolism ; Humans ; Methylation ; Mice ; Microtubule-Associated Proteins - metabolism ; Quinazolines - pharmacology ; Ribosomes - metabolism ; Serine - biosynthesis ; Serine - pharmacology ; Transcription, Genetic - drug effects</subject><ispartof>Cell metabolism, 2013-12, Vol.18 (6), p.896-907</ispartof><rights>2013 Elsevier Inc.</rights><rights>Copyright © 2013 Elsevier Inc. All rights reserved.</rights><rights>2013 Elsevier Inc. 2013</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c521t-9dca70419906ff0bb147a139dc19ebbae0cd0b70765a0e674a56145ed9daf2e33</citedby><cites>FETCH-LOGICAL-c521t-9dca70419906ff0bb147a139dc19ebbae0cd0b70765a0e674a56145ed9daf2e33</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S1550413113004531$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24315373$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ding, Jane</creatorcontrib><creatorcontrib>Li, Tai</creatorcontrib><creatorcontrib>Wang, Xiangwei</creatorcontrib><creatorcontrib>Zhao, Erhu</creatorcontrib><creatorcontrib>Choi, Jeong-Hyeon</creatorcontrib><creatorcontrib>Yang, Liqun</creatorcontrib><creatorcontrib>Zha, Yunhong</creatorcontrib><creatorcontrib>Dong, Zheng</creatorcontrib><creatorcontrib>Huang, Shuang</creatorcontrib><creatorcontrib>Asara, John M.</creatorcontrib><creatorcontrib>Cui, Hongjuan</creatorcontrib><creatorcontrib>Ding, Han-Fei</creatorcontrib><title>The Histone H3 Methyltransferase G9A Epigenetically Activates the Serine-Glycine Synthesis Pathway to Sustain Cancer Cell Survival and Proliferation</title><title>Cell metabolism</title><addtitle>Cell Metab</addtitle><description>Increased activation of the serine-glycine biosynthetic pathway is an integral part of cancer metabolism that drives macromolecule synthesis needed for cell proliferation. Whether this pathway is under epigenetic control is unknown. Here we show that the histone H3 lysine 9 (H3K9) methyltransferase G9A is required for maintaining the pathway enzyme genes in an active state marked by H3K9 monomethylation and for the transcriptional activation of this pathway in response to serine deprivation. G9A inactivation depletes serine and its downstream metabolites, triggering cell death with autophagy in cancer cell lines of different tissue origins. Higher G9A expression, which is observed in various cancers and is associated with greater mortality in cancer patients, increases serine production and enhances the proliferation and tumorigenicity of cancer cells. These findings identify a G9A-dependent epigenetic program in the control of cancer metabolism, providing a rationale for G9A inhibition as a therapeutic strategy for cancer.
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•G9A sustains cancer cell survival and proliferation•G9A epigenetically activates the serine-glycine biosynthetic pathway•G9A links serine sensing to ribosome biogenesis and cell-cycle progression•G9A has an oncogenic function in tumorigenesis</description><subject>Animals</subject><subject>Autophagy - drug effects</subject><subject>Azepines - pharmacology</subject><subject>Bone Neoplasms - metabolism</subject><subject>Bone Neoplasms - pathology</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation</subject><subject>Cell Survival - drug effects</subject><subject>Epigenomics</subject><subject>Glycine - biosynthesis</subject><subject>HeLa Cells</subject><subject>Histocompatibility Antigens - genetics</subject><subject>Histocompatibility Antigens - metabolism</subject><subject>Histone-Lysine N-Methyltransferase - antagonists & inhibitors</subject><subject>Histone-Lysine N-Methyltransferase - genetics</subject><subject>Histone-Lysine N-Methyltransferase - metabolism</subject><subject>Histones - metabolism</subject><subject>Humans</subject><subject>Methylation</subject><subject>Mice</subject><subject>Microtubule-Associated Proteins - metabolism</subject><subject>Quinazolines - pharmacology</subject><subject>Ribosomes - metabolism</subject><subject>Serine - biosynthesis</subject><subject>Serine - pharmacology</subject><subject>Transcription, Genetic - drug effects</subject><issn>1550-4131</issn><issn>1932-7420</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9Udtq3DAQNaWlubQ_0IeiH7A7Y_kSQyksS7oJpDSw6bMYy-OsFq28SMoG_0c_uFq2De1Ln85wZs4ZZk6WfUAoELD5tC30jmNRAsoCsQCoXmXn2Mkyb6sSXqe6riGvUOJZdhHCFkA2spNvs7OykljLVp5nPx82LG5MiJNLKMU3jpvZRk8ujOwpsFh1C3G9N4_sOBpN1s5ioaM5UOQgYlKv2RvH-crOOqFYzy6xwQRxT3HzTLOIk1g_hUjGiSU5zV4s2drE-UOysYLcIO79ZM1xYzSTe5e9GckGfv8bL7MfX68fljf53ffV7XJxl-u6xJh3g6YWKuw6aMYR-h6rllAmGjvue2LQA_QttE1NwE1bUd1gVfPQDTSWLOVl9uXku3_qdzxodulwq_be7MjPaiKj_u04s1GP00HJq_YK6iYZlCcD7acQPI8vWgR1zEht1TEjdcxIIaqUURJ9_Hvri-RPKGng82mA0-0Hw14FbTg9bjCedVTDZP7n_wszgKdj</recordid><startdate>20131203</startdate><enddate>20131203</enddate><creator>Ding, Jane</creator><creator>Li, Tai</creator><creator>Wang, Xiangwei</creator><creator>Zhao, Erhu</creator><creator>Choi, Jeong-Hyeon</creator><creator>Yang, Liqun</creator><creator>Zha, Yunhong</creator><creator>Dong, Zheng</creator><creator>Huang, Shuang</creator><creator>Asara, John M.</creator><creator>Cui, Hongjuan</creator><creator>Ding, Han-Fei</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</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>5PM</scope></search><sort><creationdate>20131203</creationdate><title>The Histone H3 Methyltransferase G9A Epigenetically Activates the Serine-Glycine Synthesis Pathway to Sustain Cancer Cell Survival and Proliferation</title><author>Ding, Jane ; Li, Tai ; Wang, Xiangwei ; Zhao, Erhu ; Choi, Jeong-Hyeon ; Yang, Liqun ; Zha, Yunhong ; Dong, Zheng ; Huang, Shuang ; Asara, John M. ; Cui, Hongjuan ; Ding, Han-Fei</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c521t-9dca70419906ff0bb147a139dc19ebbae0cd0b70765a0e674a56145ed9daf2e33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Animals</topic><topic>Autophagy - drug effects</topic><topic>Azepines - pharmacology</topic><topic>Bone Neoplasms - metabolism</topic><topic>Bone Neoplasms - pathology</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation</topic><topic>Cell Survival - drug effects</topic><topic>Epigenomics</topic><topic>Glycine - biosynthesis</topic><topic>HeLa Cells</topic><topic>Histocompatibility Antigens - genetics</topic><topic>Histocompatibility Antigens - metabolism</topic><topic>Histone-Lysine N-Methyltransferase - antagonists & inhibitors</topic><topic>Histone-Lysine N-Methyltransferase - genetics</topic><topic>Histone-Lysine N-Methyltransferase - metabolism</topic><topic>Histones - metabolism</topic><topic>Humans</topic><topic>Methylation</topic><topic>Mice</topic><topic>Microtubule-Associated Proteins - metabolism</topic><topic>Quinazolines - pharmacology</topic><topic>Ribosomes - metabolism</topic><topic>Serine - biosynthesis</topic><topic>Serine - pharmacology</topic><topic>Transcription, Genetic - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ding, Jane</creatorcontrib><creatorcontrib>Li, Tai</creatorcontrib><creatorcontrib>Wang, Xiangwei</creatorcontrib><creatorcontrib>Zhao, Erhu</creatorcontrib><creatorcontrib>Choi, Jeong-Hyeon</creatorcontrib><creatorcontrib>Yang, Liqun</creatorcontrib><creatorcontrib>Zha, Yunhong</creatorcontrib><creatorcontrib>Dong, Zheng</creatorcontrib><creatorcontrib>Huang, Shuang</creatorcontrib><creatorcontrib>Asara, John M.</creatorcontrib><creatorcontrib>Cui, Hongjuan</creatorcontrib><creatorcontrib>Ding, Han-Fei</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cell metabolism</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ding, Jane</au><au>Li, Tai</au><au>Wang, Xiangwei</au><au>Zhao, Erhu</au><au>Choi, Jeong-Hyeon</au><au>Yang, Liqun</au><au>Zha, Yunhong</au><au>Dong, Zheng</au><au>Huang, Shuang</au><au>Asara, John M.</au><au>Cui, Hongjuan</au><au>Ding, Han-Fei</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The Histone H3 Methyltransferase G9A Epigenetically Activates the Serine-Glycine Synthesis Pathway to Sustain Cancer Cell Survival and Proliferation</atitle><jtitle>Cell metabolism</jtitle><addtitle>Cell Metab</addtitle><date>2013-12-03</date><risdate>2013</risdate><volume>18</volume><issue>6</issue><spage>896</spage><epage>907</epage><pages>896-907</pages><issn>1550-4131</issn><eissn>1932-7420</eissn><abstract>Increased activation of the serine-glycine biosynthetic pathway is an integral part of cancer metabolism that drives macromolecule synthesis needed for cell proliferation. Whether this pathway is under epigenetic control is unknown. Here we show that the histone H3 lysine 9 (H3K9) methyltransferase G9A is required for maintaining the pathway enzyme genes in an active state marked by H3K9 monomethylation and for the transcriptional activation of this pathway in response to serine deprivation. G9A inactivation depletes serine and its downstream metabolites, triggering cell death with autophagy in cancer cell lines of different tissue origins. Higher G9A expression, which is observed in various cancers and is associated with greater mortality in cancer patients, increases serine production and enhances the proliferation and tumorigenicity of cancer cells. These findings identify a G9A-dependent epigenetic program in the control of cancer metabolism, providing a rationale for G9A inhibition as a therapeutic strategy for cancer.
[Display omitted]
•G9A sustains cancer cell survival and proliferation•G9A epigenetically activates the serine-glycine biosynthetic pathway•G9A links serine sensing to ribosome biogenesis and cell-cycle progression•G9A has an oncogenic function in tumorigenesis</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>24315373</pmid><doi>10.1016/j.cmet.2013.11.004</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Cell metabolism, 2013-12, Vol.18 (6), p.896-907 |
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| source | MEDLINE; Cell Press Free Archives; Elsevier ScienceDirect Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | Animals Autophagy - drug effects Azepines - pharmacology Bone Neoplasms - metabolism Bone Neoplasms - pathology Cell Line, Tumor Cell Proliferation Cell Survival - drug effects Epigenomics Glycine - biosynthesis HeLa Cells Histocompatibility Antigens - genetics Histocompatibility Antigens - metabolism Histone-Lysine N-Methyltransferase - antagonists & inhibitors Histone-Lysine N-Methyltransferase - genetics Histone-Lysine N-Methyltransferase - metabolism Histones - metabolism Humans Methylation Mice Microtubule-Associated Proteins - metabolism Quinazolines - pharmacology Ribosomes - metabolism Serine - biosynthesis Serine - pharmacology Transcription, Genetic - drug effects |
| title | The Histone H3 Methyltransferase G9A Epigenetically Activates the Serine-Glycine Synthesis Pathway to Sustain Cancer Cell Survival and Proliferation |
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