SP1 undergoes phase separation and activates RGS20 expression through super-enhancers to promote lung adenocarcinoma progression
Lung adenocarcinoma (LUAD) is the leading cause of cancer-related death worldwide, but the underlying molecular mechanisms remain largely unclear. The transcription factor (TF) specificity protein 1 (SP1) plays a crucial role in the development of various cancers, including LUAD. Recent studies have...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2024-07, Vol.121 (29), p.e2401834121 |
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| creator | Shan, Liying Wang, Wenmeng Du, Lijuan Li, Dangdang Wang, Yunxuan Xie, Yuyan Li, Hongyan Wang, Jiale Shi, Zhihao Zhou, Yang Zhu, Daling Sui, Guangchao Liu, Fang |
| description | Lung adenocarcinoma (LUAD) is the leading cause of cancer-related death worldwide, but the underlying molecular mechanisms remain largely unclear. The transcription factor (TF) specificity protein 1 (SP1) plays a crucial role in the development of various cancers, including LUAD. Recent studies have indicated that master TFs may form phase-separated macromolecular condensates to promote super-enhancer (SE) assembly and oncogene expression. In this study, we demonstrated that SP1 undergoes phase separation and that its zinc finger 3 in the DNA-binding domain is essential for this process. Through Cleavage Under Targets & Release Using Nuclease (CUT&RUN) using antibodies against SP1 and H3K27ac, we found a significant correlation between SP1 enrichment and SE elements, identified the regulator of the G protein signaling 20 (RGS20) gene as the most likely target regulated by SP1 through SE mechanisms, and verified this finding using different approaches. The oncogenic activity of SP1 relies on its phase separation ability and RGS20 gene activation, which can be abolished by glycogen synthase kinase J4 (GSK-J4), a demethylase inhibitor. Together, our findings provide evidence that SP1 regulates its target oncogene expression through phase separation and SE mechanisms, thereby promoting LUAD cell progression. This study also revealed an innovative target for LUAD therapies through intervening in SP1-mediated SE formation. |
| doi_str_mv | 10.1073/pnas.2401834121 |
| format | Article |
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The transcription factor (TF) specificity protein 1 (SP1) plays a crucial role in the development of various cancers, including LUAD. Recent studies have indicated that master TFs may form phase-separated macromolecular condensates to promote super-enhancer (SE) assembly and oncogene expression. In this study, we demonstrated that SP1 undergoes phase separation and that its zinc finger 3 in the DNA-binding domain is essential for this process. Through Cleavage Under Targets & Release Using Nuclease (CUT&RUN) using antibodies against SP1 and H3K27ac, we found a significant correlation between SP1 enrichment and SE elements, identified the regulator of the G protein signaling 20 (RGS20) gene as the most likely target regulated by SP1 through SE mechanisms, and verified this finding using different approaches. The oncogenic activity of SP1 relies on its phase separation ability and RGS20 gene activation, which can be abolished by glycogen synthase kinase J4 (GSK-J4), a demethylase inhibitor. Together, our findings provide evidence that SP1 regulates its target oncogene expression through phase separation and SE mechanisms, thereby promoting LUAD cell progression. This study also revealed an innovative target for LUAD therapies through intervening in SP1-mediated SE formation.</description><identifier>ISSN: 0027-8424</identifier><identifier>ISSN: 1091-6490</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.2401834121</identifier><identifier>PMID: 38976739</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Adenocarcinoma ; Adenocarcinoma of Lung - genetics ; Adenocarcinoma of Lung - metabolism ; Adenocarcinoma of Lung - pathology ; Animals ; Cancer ; Cell Line, Tumor ; Disease Progression ; Enhancer Elements, Genetic ; Enhancers ; Gene expression ; Gene Expression Regulation, Neoplastic ; Glycogen ; Glycogen synthase kinase 3 ; Glycogens ; Humans ; Kinases ; Lung cancer ; Lung Neoplasms - genetics ; Lung Neoplasms - metabolism ; Lung Neoplasms - pathology ; Lungs ; Mice ; Molecular modelling ; Nuclease ; Oncogenes ; Phase Separation ; Proteins ; RGS Proteins - genetics ; RGS Proteins - metabolism ; Sp1 protein ; Sp1 Transcription Factor - genetics ; Sp1 Transcription Factor - metabolism ; Zinc finger proteins</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2024-07, Vol.121 (29), p.e2401834121</ispartof><rights>Copyright National Academy of Sciences Jul 16, 2024</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c209t-a935bb2f4096f79d33aa919a89e592a0202fa3ff17b2c27be693e652d28569c73</cites><orcidid>0009-0009-5640-6177 ; 0000-0001-6407-9705 ; 0000-0002-8164-5585</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,782,786,27933,27934</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38976739$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Shan, Liying</creatorcontrib><creatorcontrib>Wang, Wenmeng</creatorcontrib><creatorcontrib>Du, Lijuan</creatorcontrib><creatorcontrib>Li, Dangdang</creatorcontrib><creatorcontrib>Wang, Yunxuan</creatorcontrib><creatorcontrib>Xie, Yuyan</creatorcontrib><creatorcontrib>Li, Hongyan</creatorcontrib><creatorcontrib>Wang, Jiale</creatorcontrib><creatorcontrib>Shi, Zhihao</creatorcontrib><creatorcontrib>Zhou, Yang</creatorcontrib><creatorcontrib>Zhu, Daling</creatorcontrib><creatorcontrib>Sui, Guangchao</creatorcontrib><creatorcontrib>Liu, Fang</creatorcontrib><title>SP1 undergoes phase separation and activates RGS20 expression through super-enhancers to promote lung adenocarcinoma progression</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Lung adenocarcinoma (LUAD) is the leading cause of cancer-related death worldwide, but the underlying molecular mechanisms remain largely unclear. The transcription factor (TF) specificity protein 1 (SP1) plays a crucial role in the development of various cancers, including LUAD. Recent studies have indicated that master TFs may form phase-separated macromolecular condensates to promote super-enhancer (SE) assembly and oncogene expression. In this study, we demonstrated that SP1 undergoes phase separation and that its zinc finger 3 in the DNA-binding domain is essential for this process. Through Cleavage Under Targets & Release Using Nuclease (CUT&RUN) using antibodies against SP1 and H3K27ac, we found a significant correlation between SP1 enrichment and SE elements, identified the regulator of the G protein signaling 20 (RGS20) gene as the most likely target regulated by SP1 through SE mechanisms, and verified this finding using different approaches. The oncogenic activity of SP1 relies on its phase separation ability and RGS20 gene activation, which can be abolished by glycogen synthase kinase J4 (GSK-J4), a demethylase inhibitor. Together, our findings provide evidence that SP1 regulates its target oncogene expression through phase separation and SE mechanisms, thereby promoting LUAD cell progression. This study also revealed an innovative target for LUAD therapies through intervening in SP1-mediated SE formation.</description><subject>Adenocarcinoma</subject><subject>Adenocarcinoma of Lung - genetics</subject><subject>Adenocarcinoma of Lung - metabolism</subject><subject>Adenocarcinoma of Lung - pathology</subject><subject>Animals</subject><subject>Cancer</subject><subject>Cell Line, Tumor</subject><subject>Disease Progression</subject><subject>Enhancer Elements, Genetic</subject><subject>Enhancers</subject><subject>Gene expression</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Glycogen</subject><subject>Glycogen synthase kinase 3</subject><subject>Glycogens</subject><subject>Humans</subject><subject>Kinases</subject><subject>Lung cancer</subject><subject>Lung Neoplasms - genetics</subject><subject>Lung Neoplasms - metabolism</subject><subject>Lung Neoplasms - pathology</subject><subject>Lungs</subject><subject>Mice</subject><subject>Molecular modelling</subject><subject>Nuclease</subject><subject>Oncogenes</subject><subject>Phase Separation</subject><subject>Proteins</subject><subject>RGS Proteins - genetics</subject><subject>RGS Proteins - metabolism</subject><subject>Sp1 protein</subject><subject>Sp1 Transcription Factor - genetics</subject><subject>Sp1 Transcription Factor - metabolism</subject><subject>Zinc finger proteins</subject><issn>0027-8424</issn><issn>1091-6490</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkTFP5DAQRq0TCPY46uuQJRqaLGM7ieMSIVhOQgIBV0cTZ7IbtLGDnZyOjp9OVruAROXie_ONNY-x3wLmArQ67x3GuUxBFCoVUvxgMwFGJHlqYI_NAKROilSmh-xnjM8AYLICDtihKozOtTIz9vZ4L_joagpLT5H3K4zEI_UYcGi94-hqjnZo_-EwxQ-LRwmc_veBYtzEwyr4cbnicewpJORW6CyFyAfP--A7PxBfj27JsSbnLQbbOt_hJlvuKn6x_QbXkY537xH7e331dHmT3N4t_lxe3CZWghkSNCqrKtmkYPJGm1opRCMMFoYyIxEkyAZV0whdSSt1RblRlGeylkWWG6vVETvb9k67X0aKQ9m10dJ6jY78GEsFWgudQSEm9PQb-uzH4KbfTVSh9HR5MBN1vqVs8DEGaso-tB2G11JAuZFTbuSUX3KmiZNd71h1VH_yHzbUO2YqjGc</recordid><startdate>20240716</startdate><enddate>20240716</enddate><creator>Shan, Liying</creator><creator>Wang, Wenmeng</creator><creator>Du, Lijuan</creator><creator>Li, Dangdang</creator><creator>Wang, Yunxuan</creator><creator>Xie, Yuyan</creator><creator>Li, Hongyan</creator><creator>Wang, Jiale</creator><creator>Shi, Zhihao</creator><creator>Zhou, Yang</creator><creator>Zhu, Daling</creator><creator>Sui, Guangchao</creator><creator>Liu, Fang</creator><general>National Academy of Sciences</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>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><orcidid>https://orcid.org/0009-0009-5640-6177</orcidid><orcidid>https://orcid.org/0000-0001-6407-9705</orcidid><orcidid>https://orcid.org/0000-0002-8164-5585</orcidid></search><sort><creationdate>20240716</creationdate><title>SP1 undergoes phase separation and activates RGS20 expression through super-enhancers to promote lung adenocarcinoma progression</title><author>Shan, Liying ; Wang, Wenmeng ; Du, Lijuan ; Li, Dangdang ; Wang, Yunxuan ; Xie, Yuyan ; Li, Hongyan ; Wang, Jiale ; Shi, Zhihao ; Zhou, Yang ; Zhu, Daling ; Sui, Guangchao ; Liu, Fang</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c209t-a935bb2f4096f79d33aa919a89e592a0202fa3ff17b2c27be693e652d28569c73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Adenocarcinoma</topic><topic>Adenocarcinoma of Lung - genetics</topic><topic>Adenocarcinoma of Lung - metabolism</topic><topic>Adenocarcinoma of Lung - pathology</topic><topic>Animals</topic><topic>Cancer</topic><topic>Cell Line, Tumor</topic><topic>Disease Progression</topic><topic>Enhancer Elements, Genetic</topic><topic>Enhancers</topic><topic>Gene expression</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Glycogen</topic><topic>Glycogen synthase kinase 3</topic><topic>Glycogens</topic><topic>Humans</topic><topic>Kinases</topic><topic>Lung cancer</topic><topic>Lung Neoplasms - genetics</topic><topic>Lung Neoplasms - metabolism</topic><topic>Lung Neoplasms - pathology</topic><topic>Lungs</topic><topic>Mice</topic><topic>Molecular modelling</topic><topic>Nuclease</topic><topic>Oncogenes</topic><topic>Phase Separation</topic><topic>Proteins</topic><topic>RGS Proteins - genetics</topic><topic>RGS Proteins - metabolism</topic><topic>Sp1 protein</topic><topic>Sp1 Transcription Factor - genetics</topic><topic>Sp1 Transcription Factor - metabolism</topic><topic>Zinc finger proteins</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Shan, Liying</creatorcontrib><creatorcontrib>Wang, Wenmeng</creatorcontrib><creatorcontrib>Du, Lijuan</creatorcontrib><creatorcontrib>Li, Dangdang</creatorcontrib><creatorcontrib>Wang, Yunxuan</creatorcontrib><creatorcontrib>Xie, Yuyan</creatorcontrib><creatorcontrib>Li, Hongyan</creatorcontrib><creatorcontrib>Wang, Jiale</creatorcontrib><creatorcontrib>Shi, Zhihao</creatorcontrib><creatorcontrib>Zhou, Yang</creatorcontrib><creatorcontrib>Zhu, Daling</creatorcontrib><creatorcontrib>Sui, Guangchao</creatorcontrib><creatorcontrib>Liu, Fang</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Shan, Liying</au><au>Wang, Wenmeng</au><au>Du, Lijuan</au><au>Li, Dangdang</au><au>Wang, Yunxuan</au><au>Xie, Yuyan</au><au>Li, Hongyan</au><au>Wang, Jiale</au><au>Shi, Zhihao</au><au>Zhou, Yang</au><au>Zhu, Daling</au><au>Sui, Guangchao</au><au>Liu, Fang</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>SP1 undergoes phase separation and activates RGS20 expression through super-enhancers to promote lung adenocarcinoma progression</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2024-07-16</date><risdate>2024</risdate><volume>121</volume><issue>29</issue><spage>e2401834121</spage><pages>e2401834121-</pages><issn>0027-8424</issn><issn>1091-6490</issn><eissn>1091-6490</eissn><abstract>Lung adenocarcinoma (LUAD) is the leading cause of cancer-related death worldwide, but the underlying molecular mechanisms remain largely unclear. The transcription factor (TF) specificity protein 1 (SP1) plays a crucial role in the development of various cancers, including LUAD. Recent studies have indicated that master TFs may form phase-separated macromolecular condensates to promote super-enhancer (SE) assembly and oncogene expression. In this study, we demonstrated that SP1 undergoes phase separation and that its zinc finger 3 in the DNA-binding domain is essential for this process. Through Cleavage Under Targets & Release Using Nuclease (CUT&RUN) using antibodies against SP1 and H3K27ac, we found a significant correlation between SP1 enrichment and SE elements, identified the regulator of the G protein signaling 20 (RGS20) gene as the most likely target regulated by SP1 through SE mechanisms, and verified this finding using different approaches. The oncogenic activity of SP1 relies on its phase separation ability and RGS20 gene activation, which can be abolished by glycogen synthase kinase J4 (GSK-J4), a demethylase inhibitor. Together, our findings provide evidence that SP1 regulates its target oncogene expression through phase separation and SE mechanisms, thereby promoting LUAD cell progression. This study also revealed an innovative target for LUAD therapies through intervening in SP1-mediated SE formation.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>38976739</pmid><doi>10.1073/pnas.2401834121</doi><orcidid>https://orcid.org/0009-0009-5640-6177</orcidid><orcidid>https://orcid.org/0000-0001-6407-9705</orcidid><orcidid>https://orcid.org/0000-0002-8164-5585</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Adenocarcinoma Adenocarcinoma of Lung - genetics Adenocarcinoma of Lung - metabolism Adenocarcinoma of Lung - pathology Animals Cancer Cell Line, Tumor Disease Progression Enhancer Elements, Genetic Enhancers Gene expression Gene Expression Regulation, Neoplastic Glycogen Glycogen synthase kinase 3 Glycogens Humans Kinases Lung cancer Lung Neoplasms - genetics Lung Neoplasms - metabolism Lung Neoplasms - pathology Lungs Mice Molecular modelling Nuclease Oncogenes Phase Separation Proteins RGS Proteins - genetics RGS Proteins - metabolism Sp1 protein Sp1 Transcription Factor - genetics Sp1 Transcription Factor - metabolism Zinc finger proteins |
| title | SP1 undergoes phase separation and activates RGS20 expression through super-enhancers to promote lung adenocarcinoma progression |
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