NRF2 SUMOylation promotes de novo serine synthesis and maintains HCC tumorigenesis
Nuclear factor erythroid-2 related factor 2 (NRF2) is a pivotal transcription factor that maintains cellular redox homeostasis and facilitates the development of malignant tumor phenotypes. At the molecular level, NRF2 promotes de novo serine synthesis and SUMOylation affects its function. Our resul...
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| Veröffentlicht in: | Cancer letters 2019-12, Vol.466, p.39-48 |
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| creator | Guo, Haoyan Xu, Jiaqian Zheng, Quan He, Jianli Zhou, Wei Wang, Kezhou Huang, Xian Fan, Qiuju Ma, Jiao Cheng, Jinke Mei, Wenhan Xing, Rong Cai, Rong |
| description | Nuclear factor erythroid-2 related factor 2 (NRF2) is a pivotal transcription factor that maintains cellular redox homeostasis and facilitates the development of malignant tumor phenotypes. At the molecular level, NRF2 promotes de novo serine synthesis and SUMOylation affects its function. Our results indicated that the SUMO1 acceptor site of NRF2 is the conserved lysine residue 110 (K110), and that NRF2 SUMOylation deficiency inhibited tumorigenesis in hepatocellular carcinoma (HCC). Mechanistically, NRF2 SUMOylation promoted de novo serine synthesis in HCC by enhancing the clearance of intracellular reactive oxygen species (ROS) and up-regulating phosphoglycerate dehydrogenase (PHGDH). More importantly, serine starvation increased the level of NRF2 SUMOylation, leading to sustained HCC growth. Collectively, our results indicate the presence of a novel NRF2 SUMOylation-mediated signaling process that maintains HCC tumorigenesis in normal conditions and in response to metabolic stress.
•NRF2 is conjugated by SUMO1 at K110.•NRF2 SUMOylation maintains HCC tumorigenesis.•NRF2 SUMOylation promotes de novo serine synthesis in HCC via ROS-PHGDH signaling.•Serine starvation induces NRF2 SUMOylation. |
| doi_str_mv | 10.1016/j.canlet.2019.09.010 |
| format | Article |
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•NRF2 is conjugated by SUMO1 at K110.•NRF2 SUMOylation maintains HCC tumorigenesis.•NRF2 SUMOylation promotes de novo serine synthesis in HCC via ROS-PHGDH signaling.•Serine starvation induces NRF2 SUMOylation.</description><identifier>ISSN: 0304-3835</identifier><identifier>EISSN: 1872-7980</identifier><identifier>DOI: 10.1016/j.canlet.2019.09.010</identifier><identifier>PMID: 31546024</identifier><language>eng</language><publisher>Ireland: Elsevier B.V</publisher><subject>Amino acids ; Animals ; Biosynthesis ; Cancer ; Carcinoma, Hepatocellular - metabolism ; Carcinoma, Hepatocellular - pathology ; Cell growth ; Cell Line, Tumor ; Enzymes ; Experiments ; Female ; Hep G2 Cells ; Hepatocellular carcinoma ; Homeostasis ; Humans ; Kinases ; Liver cancer ; Liver Neoplasms - metabolism ; Liver Neoplasms - pathology ; Lysine ; Metabolism ; Mice ; Mutation ; Neoplasm Transplantation ; NF-E2-Related Factor 2 - chemistry ; NF-E2-Related Factor 2 - metabolism ; Nuclear factor erythroid-2 related factor 2 ; Oxidative Stress ; Penicillin ; Phenotypes ; Phosphoglycerate dehydrogenase ; Phosphoglycerate Dehydrogenase - metabolism ; Phosphorylation ; Plasmids ; Proteins ; Reactive oxygen species ; Reactive Oxygen Species - metabolism ; Serine ; Serine - metabolism ; Serine synthesis ; Signal transduction ; Small ubiquitin-like protein ; Stress, Physiological ; SUMO protein ; Sumoylation ; Transcription factors ; Tumorigenesis</subject><ispartof>Cancer letters, 2019-12, Vol.466, p.39-48</ispartof><rights>2019 Elsevier B.V.</rights><rights>Copyright © 2019 Elsevier B.V. All rights reserved.</rights><rights>2019. Elsevier B.V.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c390t-618857966be69d5a1f8776897be1bbcbe4a8dce85258e060780a4dbed1ec40d33</citedby><cites>FETCH-LOGICAL-c390t-618857966be69d5a1f8776897be1bbcbe4a8dce85258e060780a4dbed1ec40d33</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.canlet.2019.09.010$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31546024$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Guo, Haoyan</creatorcontrib><creatorcontrib>Xu, Jiaqian</creatorcontrib><creatorcontrib>Zheng, Quan</creatorcontrib><creatorcontrib>He, Jianli</creatorcontrib><creatorcontrib>Zhou, Wei</creatorcontrib><creatorcontrib>Wang, Kezhou</creatorcontrib><creatorcontrib>Huang, Xian</creatorcontrib><creatorcontrib>Fan, Qiuju</creatorcontrib><creatorcontrib>Ma, Jiao</creatorcontrib><creatorcontrib>Cheng, Jinke</creatorcontrib><creatorcontrib>Mei, Wenhan</creatorcontrib><creatorcontrib>Xing, Rong</creatorcontrib><creatorcontrib>Cai, Rong</creatorcontrib><title>NRF2 SUMOylation promotes de novo serine synthesis and maintains HCC tumorigenesis</title><title>Cancer letters</title><addtitle>Cancer Lett</addtitle><description>Nuclear factor erythroid-2 related factor 2 (NRF2) is a pivotal transcription factor that maintains cellular redox homeostasis and facilitates the development of malignant tumor phenotypes. At the molecular level, NRF2 promotes de novo serine synthesis and SUMOylation affects its function. Our results indicated that the SUMO1 acceptor site of NRF2 is the conserved lysine residue 110 (K110), and that NRF2 SUMOylation deficiency inhibited tumorigenesis in hepatocellular carcinoma (HCC). Mechanistically, NRF2 SUMOylation promoted de novo serine synthesis in HCC by enhancing the clearance of intracellular reactive oxygen species (ROS) and up-regulating phosphoglycerate dehydrogenase (PHGDH). More importantly, serine starvation increased the level of NRF2 SUMOylation, leading to sustained HCC growth. Collectively, our results indicate the presence of a novel NRF2 SUMOylation-mediated signaling process that maintains HCC tumorigenesis in normal conditions and in response to metabolic stress.
•NRF2 is conjugated by SUMO1 at K110.•NRF2 SUMOylation maintains HCC tumorigenesis.•NRF2 SUMOylation promotes de novo serine synthesis in HCC via ROS-PHGDH signaling.•Serine starvation induces NRF2 SUMOylation.</description><subject>Amino acids</subject><subject>Animals</subject><subject>Biosynthesis</subject><subject>Cancer</subject><subject>Carcinoma, Hepatocellular - metabolism</subject><subject>Carcinoma, Hepatocellular - pathology</subject><subject>Cell growth</subject><subject>Cell Line, Tumor</subject><subject>Enzymes</subject><subject>Experiments</subject><subject>Female</subject><subject>Hep G2 Cells</subject><subject>Hepatocellular carcinoma</subject><subject>Homeostasis</subject><subject>Humans</subject><subject>Kinases</subject><subject>Liver cancer</subject><subject>Liver Neoplasms - metabolism</subject><subject>Liver Neoplasms - pathology</subject><subject>Lysine</subject><subject>Metabolism</subject><subject>Mice</subject><subject>Mutation</subject><subject>Neoplasm Transplantation</subject><subject>NF-E2-Related Factor 2 - chemistry</subject><subject>NF-E2-Related Factor 2 - metabolism</subject><subject>Nuclear factor erythroid-2 related factor 2</subject><subject>Oxidative Stress</subject><subject>Penicillin</subject><subject>Phenotypes</subject><subject>Phosphoglycerate dehydrogenase</subject><subject>Phosphoglycerate Dehydrogenase - metabolism</subject><subject>Phosphorylation</subject><subject>Plasmids</subject><subject>Proteins</subject><subject>Reactive oxygen species</subject><subject>Reactive Oxygen Species - metabolism</subject><subject>Serine</subject><subject>Serine - metabolism</subject><subject>Serine synthesis</subject><subject>Signal transduction</subject><subject>Small ubiquitin-like protein</subject><subject>Stress, Physiological</subject><subject>SUMO protein</subject><subject>Sumoylation</subject><subject>Transcription factors</subject><subject>Tumorigenesis</subject><issn>0304-3835</issn><issn>1872-7980</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kFFrFDEQx4Mo7Vn7DUQCvviy5yS7m01eBDlaK9QWWvscssmc5thNapIt3Lc3x1UffBBmmIf85p_hR8hbBmsGTHzcra0JE5Y1B6bWUIvBC7JicuDNoCS8JCtooWta2fan5HXOOwDou6E_Iact6zsBvFuRu5u7S07vH77d7idTfAz0McU5FszUIQ3xKdKMyQekeR_KT8w-UxMcnY0PpXamV5sNLcsck_-B4fD-hrzaminj-fM8Iw-XF983V8317Zevm8_XjW0VlEYwKftBCTGiUK43bCuHQUg1jMjG0Y7YGeksyp73EkHAIMF0bkTH0Hbg2vaMfDjm1ot_LZiLnn22OE0mYFyy5ryGi1b1oqLv_0F3cUmhXqd5C6C4VAIq1R0pm2LOCbf6MfnZpL1moA_O9U4fneuDcw212GHt3XP4Ms7o_i79kVyBT0cAq40nj0ln6zFYdD6hLdpF__8ffgP2MpOH</recordid><startdate>20191201</startdate><enddate>20191201</enddate><creator>Guo, Haoyan</creator><creator>Xu, Jiaqian</creator><creator>Zheng, Quan</creator><creator>He, Jianli</creator><creator>Zhou, Wei</creator><creator>Wang, Kezhou</creator><creator>Huang, Xian</creator><creator>Fan, Qiuju</creator><creator>Ma, Jiao</creator><creator>Cheng, Jinke</creator><creator>Mei, Wenhan</creator><creator>Xing, Rong</creator><creator>Cai, Rong</creator><general>Elsevier B.V</general><general>Elsevier Limited</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>7TO</scope><scope>7U9</scope><scope>H94</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>7X8</scope></search><sort><creationdate>20191201</creationdate><title>NRF2 SUMOylation promotes de novo serine synthesis and maintains HCC tumorigenesis</title><author>Guo, Haoyan ; Xu, Jiaqian ; Zheng, Quan ; He, Jianli ; Zhou, Wei ; Wang, Kezhou ; Huang, Xian ; Fan, Qiuju ; Ma, Jiao ; Cheng, Jinke ; Mei, Wenhan ; Xing, Rong ; Cai, Rong</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c390t-618857966be69d5a1f8776897be1bbcbe4a8dce85258e060780a4dbed1ec40d33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Amino acids</topic><topic>Animals</topic><topic>Biosynthesis</topic><topic>Cancer</topic><topic>Carcinoma, Hepatocellular - metabolism</topic><topic>Carcinoma, Hepatocellular - pathology</topic><topic>Cell growth</topic><topic>Cell Line, Tumor</topic><topic>Enzymes</topic><topic>Experiments</topic><topic>Female</topic><topic>Hep G2 Cells</topic><topic>Hepatocellular carcinoma</topic><topic>Homeostasis</topic><topic>Humans</topic><topic>Kinases</topic><topic>Liver cancer</topic><topic>Liver Neoplasms - metabolism</topic><topic>Liver Neoplasms - pathology</topic><topic>Lysine</topic><topic>Metabolism</topic><topic>Mice</topic><topic>Mutation</topic><topic>Neoplasm Transplantation</topic><topic>NF-E2-Related Factor 2 - chemistry</topic><topic>NF-E2-Related Factor 2 - metabolism</topic><topic>Nuclear factor erythroid-2 related factor 2</topic><topic>Oxidative Stress</topic><topic>Penicillin</topic><topic>Phenotypes</topic><topic>Phosphoglycerate dehydrogenase</topic><topic>Phosphoglycerate Dehydrogenase - metabolism</topic><topic>Phosphorylation</topic><topic>Plasmids</topic><topic>Proteins</topic><topic>Reactive oxygen species</topic><topic>Reactive Oxygen Species - metabolism</topic><topic>Serine</topic><topic>Serine - metabolism</topic><topic>Serine synthesis</topic><topic>Signal transduction</topic><topic>Small ubiquitin-like protein</topic><topic>Stress, Physiological</topic><topic>SUMO protein</topic><topic>Sumoylation</topic><topic>Transcription factors</topic><topic>Tumorigenesis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Guo, Haoyan</creatorcontrib><creatorcontrib>Xu, Jiaqian</creatorcontrib><creatorcontrib>Zheng, Quan</creatorcontrib><creatorcontrib>He, Jianli</creatorcontrib><creatorcontrib>Zhou, Wei</creatorcontrib><creatorcontrib>Wang, Kezhou</creatorcontrib><creatorcontrib>Huang, Xian</creatorcontrib><creatorcontrib>Fan, Qiuju</creatorcontrib><creatorcontrib>Ma, Jiao</creatorcontrib><creatorcontrib>Cheng, Jinke</creatorcontrib><creatorcontrib>Mei, Wenhan</creatorcontrib><creatorcontrib>Xing, Rong</creatorcontrib><creatorcontrib>Cai, Rong</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>MEDLINE - Academic</collection><jtitle>Cancer letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Guo, Haoyan</au><au>Xu, Jiaqian</au><au>Zheng, Quan</au><au>He, Jianli</au><au>Zhou, Wei</au><au>Wang, Kezhou</au><au>Huang, Xian</au><au>Fan, Qiuju</au><au>Ma, Jiao</au><au>Cheng, Jinke</au><au>Mei, Wenhan</au><au>Xing, Rong</au><au>Cai, Rong</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>NRF2 SUMOylation promotes de novo serine synthesis and maintains HCC tumorigenesis</atitle><jtitle>Cancer letters</jtitle><addtitle>Cancer Lett</addtitle><date>2019-12-01</date><risdate>2019</risdate><volume>466</volume><spage>39</spage><epage>48</epage><pages>39-48</pages><issn>0304-3835</issn><eissn>1872-7980</eissn><abstract>Nuclear factor erythroid-2 related factor 2 (NRF2) is a pivotal transcription factor that maintains cellular redox homeostasis and facilitates the development of malignant tumor phenotypes. At the molecular level, NRF2 promotes de novo serine synthesis and SUMOylation affects its function. Our results indicated that the SUMO1 acceptor site of NRF2 is the conserved lysine residue 110 (K110), and that NRF2 SUMOylation deficiency inhibited tumorigenesis in hepatocellular carcinoma (HCC). Mechanistically, NRF2 SUMOylation promoted de novo serine synthesis in HCC by enhancing the clearance of intracellular reactive oxygen species (ROS) and up-regulating phosphoglycerate dehydrogenase (PHGDH). More importantly, serine starvation increased the level of NRF2 SUMOylation, leading to sustained HCC growth. Collectively, our results indicate the presence of a novel NRF2 SUMOylation-mediated signaling process that maintains HCC tumorigenesis in normal conditions and in response to metabolic stress.
•NRF2 is conjugated by SUMO1 at K110.•NRF2 SUMOylation maintains HCC tumorigenesis.•NRF2 SUMOylation promotes de novo serine synthesis in HCC via ROS-PHGDH signaling.•Serine starvation induces NRF2 SUMOylation.</abstract><cop>Ireland</cop><pub>Elsevier B.V</pub><pmid>31546024</pmid><doi>10.1016/j.canlet.2019.09.010</doi><tpages>10</tpages></addata></record> |
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| subjects | Amino acids Animals Biosynthesis Cancer Carcinoma, Hepatocellular - metabolism Carcinoma, Hepatocellular - pathology Cell growth Cell Line, Tumor Enzymes Experiments Female Hep G2 Cells Hepatocellular carcinoma Homeostasis Humans Kinases Liver cancer Liver Neoplasms - metabolism Liver Neoplasms - pathology Lysine Metabolism Mice Mutation Neoplasm Transplantation NF-E2-Related Factor 2 - chemistry NF-E2-Related Factor 2 - metabolism Nuclear factor erythroid-2 related factor 2 Oxidative Stress Penicillin Phenotypes Phosphoglycerate dehydrogenase Phosphoglycerate Dehydrogenase - metabolism Phosphorylation Plasmids Proteins Reactive oxygen species Reactive Oxygen Species - metabolism Serine Serine - metabolism Serine synthesis Signal transduction Small ubiquitin-like protein Stress, Physiological SUMO protein Sumoylation Transcription factors Tumorigenesis |
| title | NRF2 SUMOylation promotes de novo serine synthesis and maintains HCC tumorigenesis |
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