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DCAF13 promotes ovarian cancer progression by activating FRAS1-mediated FAK signaling pathway
Cullin-RING ubiquitin ligase 4 (CRL4) is closely correlated with the incidence and progression of ovarian cancer. DDB1- and CUL4-associated factor 13 (DCAF13), a substrate-recognition protein in the CRL4 E3 ubiquitin ligase complex, is involved in the occurrence and development of ovarian cancer. Ho...
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Published in: | Cellular and molecular life sciences : CMLS 2024-12, Vol.81 (1), p.421, Article 421 |
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creator | Tang, Ze-Yi Wang, Xiao-Min Xu, Chun-Wei Sun, Qing-Qing Hua, Yu-Xin Zhou, Qi-Yin Hu, Han-Yin Liu, Sheng-Bing Guo, Yan-Jun Ao, Lei Che, Xuan Zhang, Xian-Chao Heger, Michal Zheng, Xin Liu, Ai-Jun Wang, Qian Zhan, Zha-Jun Cheng, Shu-Qun Pan, Wei-Wei |
description | Cullin-RING ubiquitin ligase 4 (CRL4) is closely correlated with the incidence and progression of ovarian cancer. DDB1- and CUL4-associated factor 13 (DCAF13), a substrate-recognition protein in the CRL4 E3 ubiquitin ligase complex, is involved in the occurrence and development of ovarian cancer. However, its precise function and the underlying molecular mechanism in this disease remain unclear. In this study, we confirmed that DCAF13 is highly expressed in human ovarian cancer and its expression is negatively correlated with the overall survival rate of patients with ovarian cancer. We then used CRISPR/Cas9 to knockout DCAF13 and found that its deletion significantly inhibited the proliferation, colony formation, and migration of human ovarian cancer cells. In addition, DCAF13 deficiency inhibited tumor proliferation in nude mice. Mechanistically, CRL4-DCAF13 targeted Fraser extracellular matrix complex subunit 1 (FRAS1) for polyubiquitination and proteasomal degradation. FRAS1 influenced the proliferation and migration of ovarian cancer cell through induction of the focal adhesion kinase (FAK) signaling pathway. These findings collectively show that DCAF13 is an important oncogene that promotes tumorigenesis in ovarian cancer cells by mediating FRAS1/FAK signaling. Our findings provide a foundation for the development of targeted therapeutics for ovarian cancer. |
doi_str_mv | 10.1007/s00018-024-05446-2 |
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DDB1- and CUL4-associated factor 13 (DCAF13), a substrate-recognition protein in the CRL4 E3 ubiquitin ligase complex, is involved in the occurrence and development of ovarian cancer. However, its precise function and the underlying molecular mechanism in this disease remain unclear. In this study, we confirmed that DCAF13 is highly expressed in human ovarian cancer and its expression is negatively correlated with the overall survival rate of patients with ovarian cancer. We then used CRISPR/Cas9 to knockout DCAF13 and found that its deletion significantly inhibited the proliferation, colony formation, and migration of human ovarian cancer cells. In addition, DCAF13 deficiency inhibited tumor proliferation in nude mice. Mechanistically, CRL4-DCAF13 targeted Fraser extracellular matrix complex subunit 1 (FRAS1) for polyubiquitination and proteasomal degradation. FRAS1 influenced the proliferation and migration of ovarian cancer cell through induction of the focal adhesion kinase (FAK) signaling pathway. These findings collectively show that DCAF13 is an important oncogene that promotes tumorigenesis in ovarian cancer cells by mediating FRAS1/FAK signaling. Our findings provide a foundation for the development of targeted therapeutics for ovarian cancer.</description><identifier>ISSN: 1420-682X</identifier><identifier>ISSN: 1420-9071</identifier><identifier>EISSN: 1420-9071</identifier><identifier>DOI: 10.1007/s00018-024-05446-2</identifier><identifier>PMID: 39367995</identifier><language>eng</language><publisher>Cham: Springer International Publishing</publisher><subject>Animals ; Biochemistry ; Biomedical and Life Sciences ; Biomedicine ; Cancer ; Cell Biology ; Cell Line, Tumor ; Cell migration ; Cell Movement - genetics ; Cell Proliferation ; Clonal deletion ; CRISPR ; Cullin ; Disease Progression ; Drug development ; Extracellular matrix ; Extracellular Matrix Proteins - metabolism ; Female ; Focal adhesion kinase ; Focal Adhesion Kinase 1 - genetics ; Focal Adhesion Kinase 1 - metabolism ; Gene Expression Regulation, Neoplastic ; Humans ; Kinases ; Life Sciences ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Molecular modelling ; Original ; Original Article ; Ovarian cancer ; Ovarian Neoplasms - genetics ; Ovarian Neoplasms - metabolism ; Ovarian Neoplasms - pathology ; Proteasomes ; RNA-Binding Proteins - metabolism ; Signal Transduction ; Substrates ; Survival ; Tumorigenesis ; Ubiquitin-protein ligase ; Ubiquitination</subject><ispartof>Cellular and molecular life sciences : CMLS, 2024-12, Vol.81 (1), p.421, Article 421</ispartof><rights>The Author(s) 2024</rights><rights>2024. The Author(s).</rights><rights>The Author(s) 2024. This work is published under http://creativecommons.org/licenses/by-nc-nd/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>The Author(s) 2024 2024</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c356t-de644f5dee90226c7f6f8c5d483e8a42942bf8a985dc4f7c43212f459c3771a63</cites><orcidid>0000-0002-3574-3758</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC11455852/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC11455852/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39367995$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Tang, Ze-Yi</creatorcontrib><creatorcontrib>Wang, Xiao-Min</creatorcontrib><creatorcontrib>Xu, Chun-Wei</creatorcontrib><creatorcontrib>Sun, Qing-Qing</creatorcontrib><creatorcontrib>Hua, Yu-Xin</creatorcontrib><creatorcontrib>Zhou, Qi-Yin</creatorcontrib><creatorcontrib>Hu, Han-Yin</creatorcontrib><creatorcontrib>Liu, Sheng-Bing</creatorcontrib><creatorcontrib>Guo, Yan-Jun</creatorcontrib><creatorcontrib>Ao, Lei</creatorcontrib><creatorcontrib>Che, Xuan</creatorcontrib><creatorcontrib>Zhang, Xian-Chao</creatorcontrib><creatorcontrib>Heger, Michal</creatorcontrib><creatorcontrib>Zheng, Xin</creatorcontrib><creatorcontrib>Liu, Ai-Jun</creatorcontrib><creatorcontrib>Wang, Qian</creatorcontrib><creatorcontrib>Zhan, Zha-Jun</creatorcontrib><creatorcontrib>Cheng, Shu-Qun</creatorcontrib><creatorcontrib>Pan, Wei-Wei</creatorcontrib><title>DCAF13 promotes ovarian cancer progression by activating FRAS1-mediated FAK signaling pathway</title><title>Cellular and molecular life sciences : CMLS</title><addtitle>Cell. Mol. Life Sci</addtitle><addtitle>Cell Mol Life Sci</addtitle><description>Cullin-RING ubiquitin ligase 4 (CRL4) is closely correlated with the incidence and progression of ovarian cancer. DDB1- and CUL4-associated factor 13 (DCAF13), a substrate-recognition protein in the CRL4 E3 ubiquitin ligase complex, is involved in the occurrence and development of ovarian cancer. However, its precise function and the underlying molecular mechanism in this disease remain unclear. In this study, we confirmed that DCAF13 is highly expressed in human ovarian cancer and its expression is negatively correlated with the overall survival rate of patients with ovarian cancer. We then used CRISPR/Cas9 to knockout DCAF13 and found that its deletion significantly inhibited the proliferation, colony formation, and migration of human ovarian cancer cells. In addition, DCAF13 deficiency inhibited tumor proliferation in nude mice. Mechanistically, CRL4-DCAF13 targeted Fraser extracellular matrix complex subunit 1 (FRAS1) for polyubiquitination and proteasomal degradation. FRAS1 influenced the proliferation and migration of ovarian cancer cell through induction of the focal adhesion kinase (FAK) signaling pathway. These findings collectively show that DCAF13 is an important oncogene that promotes tumorigenesis in ovarian cancer cells by mediating FRAS1/FAK signaling. Our findings provide a foundation for the development of targeted therapeutics for ovarian cancer.</description><subject>Animals</subject><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Cancer</subject><subject>Cell Biology</subject><subject>Cell Line, Tumor</subject><subject>Cell migration</subject><subject>Cell Movement - genetics</subject><subject>Cell Proliferation</subject><subject>Clonal deletion</subject><subject>CRISPR</subject><subject>Cullin</subject><subject>Disease Progression</subject><subject>Drug development</subject><subject>Extracellular matrix</subject><subject>Extracellular Matrix Proteins - metabolism</subject><subject>Female</subject><subject>Focal adhesion kinase</subject><subject>Focal Adhesion Kinase 1 - genetics</subject><subject>Focal Adhesion Kinase 1 - metabolism</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Humans</subject><subject>Kinases</subject><subject>Life Sciences</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Mice, Nude</subject><subject>Molecular modelling</subject><subject>Original</subject><subject>Original Article</subject><subject>Ovarian cancer</subject><subject>Ovarian Neoplasms - genetics</subject><subject>Ovarian Neoplasms - metabolism</subject><subject>Ovarian Neoplasms - pathology</subject><subject>Proteasomes</subject><subject>RNA-Binding Proteins - metabolism</subject><subject>Signal Transduction</subject><subject>Substrates</subject><subject>Survival</subject><subject>Tumorigenesis</subject><subject>Ubiquitin-protein ligase</subject><subject>Ubiquitination</subject><issn>1420-682X</issn><issn>1420-9071</issn><issn>1420-9071</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><recordid>eNp9kUtvEzEUha0K1JbSP9AFGokNmwG_x16hKBBAVKrEQ2JTWTcez9TVxE7tSVD-PU4ntMCClS2fz-eeq4PQBcGvCcbNm4wxJqrGlNdYcC5reoROCae41rghTw53qeiPE_Qs59tCC0XlMTphmslGa3GKrt_NZwvCqnWKqzi6XMUtJA-hshCsS_v3PrmcfQzVcleBHf0WRh_6avFl9pXUK9d6GF1bLWafq-z7AMNeXMN48xN2z9HTDobszg_nGfq-eP9t_rG-vPrwaT67rC0TcqxbJznvROucxpRK23SyU1a0XDGngFPN6bJToJVoLe8ayxkltONCW9Y0BCQ7Q28n3_VmWRJZF8YEg1knv4K0MxG8-VsJ_sb0cWsI4UIoQYvDq4NDincbl0ez8tm6YYDg4iYbRghjitBGF_TlP-ht3KSy-EQRLZlghaITZVPMObnuIQ3BZl-fmeozpT5zX5_Zp3jx5x4PX373VQA2AblIoXfpcfZ_bH8BxSmlYg</recordid><startdate>20241201</startdate><enddate>20241201</enddate><creator>Tang, Ze-Yi</creator><creator>Wang, Xiao-Min</creator><creator>Xu, Chun-Wei</creator><creator>Sun, Qing-Qing</creator><creator>Hua, Yu-Xin</creator><creator>Zhou, Qi-Yin</creator><creator>Hu, Han-Yin</creator><creator>Liu, Sheng-Bing</creator><creator>Guo, Yan-Jun</creator><creator>Ao, Lei</creator><creator>Che, Xuan</creator><creator>Zhang, Xian-Chao</creator><creator>Heger, Michal</creator><creator>Zheng, Xin</creator><creator>Liu, Ai-Jun</creator><creator>Wang, Qian</creator><creator>Zhan, Zha-Jun</creator><creator>Cheng, Shu-Qun</creator><creator>Pan, Wei-Wei</creator><general>Springer International Publishing</general><general>Springer Nature B.V</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>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SS</scope><scope>7T5</scope><scope>7T7</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U7</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-3574-3758</orcidid></search><sort><creationdate>20241201</creationdate><title>DCAF13 promotes ovarian cancer progression by activating FRAS1-mediated FAK signaling pathway</title><author>Tang, Ze-Yi ; Wang, Xiao-Min ; Xu, Chun-Wei ; Sun, Qing-Qing ; Hua, Yu-Xin ; Zhou, Qi-Yin ; Hu, Han-Yin ; Liu, Sheng-Bing ; Guo, Yan-Jun ; Ao, Lei ; Che, Xuan ; Zhang, Xian-Chao ; Heger, Michal ; Zheng, Xin ; Liu, Ai-Jun ; Wang, Qian ; Zhan, Zha-Jun ; Cheng, Shu-Qun ; Pan, Wei-Wei</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c356t-de644f5dee90226c7f6f8c5d483e8a42942bf8a985dc4f7c43212f459c3771a63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Animals</topic><topic>Biochemistry</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Cancer</topic><topic>Cell Biology</topic><topic>Cell Line, Tumor</topic><topic>Cell migration</topic><topic>Cell Movement - genetics</topic><topic>Cell Proliferation</topic><topic>Clonal deletion</topic><topic>CRISPR</topic><topic>Cullin</topic><topic>Disease Progression</topic><topic>Drug development</topic><topic>Extracellular matrix</topic><topic>Extracellular Matrix Proteins - metabolism</topic><topic>Female</topic><topic>Focal adhesion kinase</topic><topic>Focal Adhesion Kinase 1 - genetics</topic><topic>Focal Adhesion Kinase 1 - metabolism</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Humans</topic><topic>Kinases</topic><topic>Life Sciences</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Mice, Nude</topic><topic>Molecular modelling</topic><topic>Original</topic><topic>Original Article</topic><topic>Ovarian cancer</topic><topic>Ovarian Neoplasms - genetics</topic><topic>Ovarian Neoplasms - metabolism</topic><topic>Ovarian Neoplasms - pathology</topic><topic>Proteasomes</topic><topic>RNA-Binding Proteins - metabolism</topic><topic>Signal Transduction</topic><topic>Substrates</topic><topic>Survival</topic><topic>Tumorigenesis</topic><topic>Ubiquitin-protein ligase</topic><topic>Ubiquitination</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Tang, Ze-Yi</creatorcontrib><creatorcontrib>Wang, Xiao-Min</creatorcontrib><creatorcontrib>Xu, Chun-Wei</creatorcontrib><creatorcontrib>Sun, Qing-Qing</creatorcontrib><creatorcontrib>Hua, Yu-Xin</creatorcontrib><creatorcontrib>Zhou, Qi-Yin</creatorcontrib><creatorcontrib>Hu, Han-Yin</creatorcontrib><creatorcontrib>Liu, Sheng-Bing</creatorcontrib><creatorcontrib>Guo, Yan-Jun</creatorcontrib><creatorcontrib>Ao, Lei</creatorcontrib><creatorcontrib>Che, Xuan</creatorcontrib><creatorcontrib>Zhang, Xian-Chao</creatorcontrib><creatorcontrib>Heger, Michal</creatorcontrib><creatorcontrib>Zheng, Xin</creatorcontrib><creatorcontrib>Liu, Ai-Jun</creatorcontrib><creatorcontrib>Wang, Qian</creatorcontrib><creatorcontrib>Zhan, Zha-Jun</creatorcontrib><creatorcontrib>Cheng, Shu-Qun</creatorcontrib><creatorcontrib>Pan, Wei-Wei</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>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Toxicology 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>ProQuest Health & Medical Complete (Alumni)</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cellular and molecular life sciences : CMLS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tang, Ze-Yi</au><au>Wang, Xiao-Min</au><au>Xu, Chun-Wei</au><au>Sun, Qing-Qing</au><au>Hua, Yu-Xin</au><au>Zhou, Qi-Yin</au><au>Hu, Han-Yin</au><au>Liu, Sheng-Bing</au><au>Guo, Yan-Jun</au><au>Ao, Lei</au><au>Che, Xuan</au><au>Zhang, Xian-Chao</au><au>Heger, Michal</au><au>Zheng, Xin</au><au>Liu, Ai-Jun</au><au>Wang, Qian</au><au>Zhan, Zha-Jun</au><au>Cheng, Shu-Qun</au><au>Pan, Wei-Wei</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>DCAF13 promotes ovarian cancer progression by activating FRAS1-mediated FAK signaling pathway</atitle><jtitle>Cellular and molecular life sciences : CMLS</jtitle><stitle>Cell. Mol. Life Sci</stitle><addtitle>Cell Mol Life Sci</addtitle><date>2024-12-01</date><risdate>2024</risdate><volume>81</volume><issue>1</issue><spage>421</spage><pages>421-</pages><artnum>421</artnum><issn>1420-682X</issn><issn>1420-9071</issn><eissn>1420-9071</eissn><abstract>Cullin-RING ubiquitin ligase 4 (CRL4) is closely correlated with the incidence and progression of ovarian cancer. DDB1- and CUL4-associated factor 13 (DCAF13), a substrate-recognition protein in the CRL4 E3 ubiquitin ligase complex, is involved in the occurrence and development of ovarian cancer. However, its precise function and the underlying molecular mechanism in this disease remain unclear. In this study, we confirmed that DCAF13 is highly expressed in human ovarian cancer and its expression is negatively correlated with the overall survival rate of patients with ovarian cancer. We then used CRISPR/Cas9 to knockout DCAF13 and found that its deletion significantly inhibited the proliferation, colony formation, and migration of human ovarian cancer cells. In addition, DCAF13 deficiency inhibited tumor proliferation in nude mice. Mechanistically, CRL4-DCAF13 targeted Fraser extracellular matrix complex subunit 1 (FRAS1) for polyubiquitination and proteasomal degradation. FRAS1 influenced the proliferation and migration of ovarian cancer cell through induction of the focal adhesion kinase (FAK) signaling pathway. These findings collectively show that DCAF13 is an important oncogene that promotes tumorigenesis in ovarian cancer cells by mediating FRAS1/FAK signaling. Our findings provide a foundation for the development of targeted therapeutics for ovarian cancer.</abstract><cop>Cham</cop><pub>Springer International Publishing</pub><pmid>39367995</pmid><doi>10.1007/s00018-024-05446-2</doi><orcidid>https://orcid.org/0000-0002-3574-3758</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Animals Biochemistry Biomedical and Life Sciences Biomedicine Cancer Cell Biology Cell Line, Tumor Cell migration Cell Movement - genetics Cell Proliferation Clonal deletion CRISPR Cullin Disease Progression Drug development Extracellular matrix Extracellular Matrix Proteins - metabolism Female Focal adhesion kinase Focal Adhesion Kinase 1 - genetics Focal Adhesion Kinase 1 - metabolism Gene Expression Regulation, Neoplastic Humans Kinases Life Sciences Mice Mice, Inbred BALB C Mice, Nude Molecular modelling Original Original Article Ovarian cancer Ovarian Neoplasms - genetics Ovarian Neoplasms - metabolism Ovarian Neoplasms - pathology Proteasomes RNA-Binding Proteins - metabolism Signal Transduction Substrates Survival Tumorigenesis Ubiquitin-protein ligase Ubiquitination |
title | DCAF13 promotes ovarian cancer progression by activating FRAS1-mediated FAK signaling pathway |
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