Smad4 sequestered in SFPQ condensates prevents TGF-β tumor-suppressive signaling
Loss of TGF-β growth-inhibitory responses is a hallmark of human cancer. However, the molecular mechanisms underlying the TGF-β resistance of cancer cells remain to be fully elucidated. Splicing factor proline- and glutamine-rich (SFPQ) is a prion-like RNA-binding protein that is frequently upregula...
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Veröffentlicht in: | Developmental cell 2024-01, Vol.59 (1), p.48-63.e8 |
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container_title | Developmental cell |
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creator | Xiao, Mu Wang, Fei Chen, Nuo Zhang, Hanchenxi Cao, Jin Yu, Yi Zhao, Bin Ji, Junfang Xu, Pinglong Li, Lei Shen, Li Lin, Xia Feng, Xin-Hua |
description | Loss of TGF-β growth-inhibitory responses is a hallmark of human cancer. However, the molecular mechanisms underlying the TGF-β resistance of cancer cells remain to be fully elucidated. Splicing factor proline- and glutamine-rich (SFPQ) is a prion-like RNA-binding protein that is frequently upregulated in human cancers. In this study, we identified SFPQ as a potent suppressor of TGF-β signaling. The ability of SFPQ to suppress TGF-β responses depends on its prion-like domain (PrLD) that drives liquid-liquid phase separation (LLPS). Mechanistically, SFPQ physically restrained Smad4 in its condensates, which excluded Smad4 from the Smad complex and chromatin occupancy and thus functionally dampened Smad-dependent transcriptional responses. Accordingly, SFPQ deficiency or loss of phase separation activities rendered human cells hypersensitive to TGF-β responses. Together, our data identify an important function of SFPQ through LLPS that suppresses Smad transcriptional activation and TGF-β tumor-suppressive activity. |
doi_str_mv | 10.1016/j.devcel.2023.11.020 |
format | Article |
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However, the molecular mechanisms underlying the TGF-β resistance of cancer cells remain to be fully elucidated. Splicing factor proline- and glutamine-rich (SFPQ) is a prion-like RNA-binding protein that is frequently upregulated in human cancers. In this study, we identified SFPQ as a potent suppressor of TGF-β signaling. The ability of SFPQ to suppress TGF-β responses depends on its prion-like domain (PrLD) that drives liquid-liquid phase separation (LLPS). Mechanistically, SFPQ physically restrained Smad4 in its condensates, which excluded Smad4 from the Smad complex and chromatin occupancy and thus functionally dampened Smad-dependent transcriptional responses. Accordingly, SFPQ deficiency or loss of phase separation activities rendered human cells hypersensitive to TGF-β responses. Together, our data identify an important function of SFPQ through LLPS that suppresses Smad transcriptional activation and TGF-β tumor-suppressive activity.</description><identifier>ISSN: 1534-5807</identifier><identifier>EISSN: 1878-1551</identifier><identifier>DOI: 10.1016/j.devcel.2023.11.020</identifier><identifier>PMID: 38103553</identifier><language>eng</language><publisher>United States</publisher><subject>Humans ; Neoplasms ; Prions ; RNA-Binding Proteins ; Smad4 Protein - genetics ; Smad4 Protein - metabolism ; Transcriptional Activation ; Transforming Growth Factor beta - metabolism</subject><ispartof>Developmental cell, 2024-01, Vol.59 (1), p.48-63.e8</ispartof><rights>Copyright © 2023 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c307t-4f8c8885c4170452af428b6b4eabdf88248d4dcde5016167437bae478a7edfbc3</citedby><cites>FETCH-LOGICAL-c307t-4f8c8885c4170452af428b6b4eabdf88248d4dcde5016167437bae478a7edfbc3</cites><orcidid>0000-0002-4418-0811</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27903,27904</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38103553$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Xiao, Mu</creatorcontrib><creatorcontrib>Wang, Fei</creatorcontrib><creatorcontrib>Chen, Nuo</creatorcontrib><creatorcontrib>Zhang, Hanchenxi</creatorcontrib><creatorcontrib>Cao, Jin</creatorcontrib><creatorcontrib>Yu, Yi</creatorcontrib><creatorcontrib>Zhao, Bin</creatorcontrib><creatorcontrib>Ji, Junfang</creatorcontrib><creatorcontrib>Xu, Pinglong</creatorcontrib><creatorcontrib>Li, Lei</creatorcontrib><creatorcontrib>Shen, Li</creatorcontrib><creatorcontrib>Lin, Xia</creatorcontrib><creatorcontrib>Feng, Xin-Hua</creatorcontrib><title>Smad4 sequestered in SFPQ condensates prevents TGF-β tumor-suppressive signaling</title><title>Developmental cell</title><addtitle>Dev Cell</addtitle><description>Loss of TGF-β growth-inhibitory responses is a hallmark of human cancer. However, the molecular mechanisms underlying the TGF-β resistance of cancer cells remain to be fully elucidated. Splicing factor proline- and glutamine-rich (SFPQ) is a prion-like RNA-binding protein that is frequently upregulated in human cancers. In this study, we identified SFPQ as a potent suppressor of TGF-β signaling. The ability of SFPQ to suppress TGF-β responses depends on its prion-like domain (PrLD) that drives liquid-liquid phase separation (LLPS). Mechanistically, SFPQ physically restrained Smad4 in its condensates, which excluded Smad4 from the Smad complex and chromatin occupancy and thus functionally dampened Smad-dependent transcriptional responses. Accordingly, SFPQ deficiency or loss of phase separation activities rendered human cells hypersensitive to TGF-β responses. Together, our data identify an important function of SFPQ through LLPS that suppresses Smad transcriptional activation and TGF-β tumor-suppressive activity.</description><subject>Humans</subject><subject>Neoplasms</subject><subject>Prions</subject><subject>RNA-Binding Proteins</subject><subject>Smad4 Protein - genetics</subject><subject>Smad4 Protein - metabolism</subject><subject>Transcriptional Activation</subject><subject>Transforming Growth Factor beta - metabolism</subject><issn>1534-5807</issn><issn>1878-1551</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kN1KAzEQhYMotlbfQCSX3uya3028lGKrUNDSeh2yyWzZsj812S34Wj6Iz-TWqldzYM6ZOXwIXVOSUkKzu23qYe-gShlhPKU0JYycoDHVSidUSno6aMlFIjVRI3QR45YMMarJORpxTQmXko_RclVbL3CE9x5iBwE8Lhu8mr0usWsbD020HUS8C7CHpot4PZ8lX5-46-s2JLHfDYsYyz3gWG4aW5XN5hKdFbaKcPU7J-ht9riePiWLl_nz9GGROE5Ul4hCO621dIIqIiSzhWA6z3IBNveF1kxoL7zzIA-tMyW4yi0Ipa0CX-SOT9Dt8e4utD_lTV3GgUdlG2j7aNg94ZxljJDBKo5WF9oYAxRmF8rahg9DiTnANFtzhGkOMA2lZoA5xG5-P_R5Df4_9EePfwOQzXMx</recordid><startdate>20240108</startdate><enddate>20240108</enddate><creator>Xiao, Mu</creator><creator>Wang, Fei</creator><creator>Chen, Nuo</creator><creator>Zhang, Hanchenxi</creator><creator>Cao, Jin</creator><creator>Yu, Yi</creator><creator>Zhao, Bin</creator><creator>Ji, Junfang</creator><creator>Xu, Pinglong</creator><creator>Li, Lei</creator><creator>Shen, Li</creator><creator>Lin, Xia</creator><creator>Feng, Xin-Hua</creator><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>7X8</scope><orcidid>https://orcid.org/0000-0002-4418-0811</orcidid></search><sort><creationdate>20240108</creationdate><title>Smad4 sequestered in SFPQ condensates prevents TGF-β tumor-suppressive signaling</title><author>Xiao, Mu ; Wang, Fei ; Chen, Nuo ; Zhang, Hanchenxi ; Cao, Jin ; Yu, Yi ; Zhao, Bin ; Ji, Junfang ; Xu, Pinglong ; Li, Lei ; Shen, Li ; Lin, Xia ; Feng, Xin-Hua</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c307t-4f8c8885c4170452af428b6b4eabdf88248d4dcde5016167437bae478a7edfbc3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Humans</topic><topic>Neoplasms</topic><topic>Prions</topic><topic>RNA-Binding Proteins</topic><topic>Smad4 Protein - genetics</topic><topic>Smad4 Protein - metabolism</topic><topic>Transcriptional Activation</topic><topic>Transforming Growth Factor beta - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Xiao, Mu</creatorcontrib><creatorcontrib>Wang, Fei</creatorcontrib><creatorcontrib>Chen, Nuo</creatorcontrib><creatorcontrib>Zhang, Hanchenxi</creatorcontrib><creatorcontrib>Cao, Jin</creatorcontrib><creatorcontrib>Yu, Yi</creatorcontrib><creatorcontrib>Zhao, Bin</creatorcontrib><creatorcontrib>Ji, Junfang</creatorcontrib><creatorcontrib>Xu, Pinglong</creatorcontrib><creatorcontrib>Li, Lei</creatorcontrib><creatorcontrib>Shen, Li</creatorcontrib><creatorcontrib>Lin, Xia</creatorcontrib><creatorcontrib>Feng, Xin-Hua</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Developmental cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Xiao, Mu</au><au>Wang, Fei</au><au>Chen, Nuo</au><au>Zhang, Hanchenxi</au><au>Cao, Jin</au><au>Yu, Yi</au><au>Zhao, Bin</au><au>Ji, Junfang</au><au>Xu, Pinglong</au><au>Li, Lei</au><au>Shen, Li</au><au>Lin, Xia</au><au>Feng, Xin-Hua</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Smad4 sequestered in SFPQ condensates prevents TGF-β tumor-suppressive signaling</atitle><jtitle>Developmental cell</jtitle><addtitle>Dev Cell</addtitle><date>2024-01-08</date><risdate>2024</risdate><volume>59</volume><issue>1</issue><spage>48</spage><epage>63.e8</epage><pages>48-63.e8</pages><issn>1534-5807</issn><eissn>1878-1551</eissn><abstract>Loss of TGF-β growth-inhibitory responses is a hallmark of human cancer. However, the molecular mechanisms underlying the TGF-β resistance of cancer cells remain to be fully elucidated. Splicing factor proline- and glutamine-rich (SFPQ) is a prion-like RNA-binding protein that is frequently upregulated in human cancers. In this study, we identified SFPQ as a potent suppressor of TGF-β signaling. The ability of SFPQ to suppress TGF-β responses depends on its prion-like domain (PrLD) that drives liquid-liquid phase separation (LLPS). Mechanistically, SFPQ physically restrained Smad4 in its condensates, which excluded Smad4 from the Smad complex and chromatin occupancy and thus functionally dampened Smad-dependent transcriptional responses. Accordingly, SFPQ deficiency or loss of phase separation activities rendered human cells hypersensitive to TGF-β responses. 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subjects | Humans Neoplasms Prions RNA-Binding Proteins Smad4 Protein - genetics Smad4 Protein - metabolism Transcriptional Activation Transforming Growth Factor beta - metabolism |
title | Smad4 sequestered in SFPQ condensates prevents TGF-β tumor-suppressive signaling |
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