Differentiation-inducing factor-1 inhibits EMT by proteasomal degradation of TAZ and YAP in cervical and colon cancer cell lines
We previously reported differentiation-inducing factor-1 (DIF-1) activated glycogen synthase kinase-3 (GSK-3) in various mammalian cells. GSK-3 has been proposed to regulate a number of signaling pathway including TAZ/YAP signaling pathway. To clarify the effect of DIF-1 on TAZ/YAP signaling pathway...
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| creator | Arioka, Masaki Yi, Wang Igawa, Kazunobu Ishikane, Shin Takahashi-Yanaga, Fumi |
| description | We previously reported differentiation-inducing factor-1 (DIF-1) activated glycogen synthase kinase-3 (GSK-3) in various mammalian cells. GSK-3 has been proposed to regulate a number of signaling pathway including TAZ/YAP signaling pathway. To clarify the effect of DIF-1 on TAZ/YAP signaling pathway, we examined whether DIF-1 affect the expression levels of TAZ and YAP. We found that DIF-1-induced proteasomal- and GSK-3-dependent degradation of both TAZ and YAP in human cervical cancer cell line HeLa in a time- and dose-dependent manner. As TAZ/YAP signaling pathway is well known to accelerate the epithelial-mesenchymal transition (EMT) of the cancer cell, we examined the effect of TAZ/YAP signaling pathway on EMT-related proteins. Knockdown of TAZ and YAP proteins by siRNA significantly reduced the expression of fibronectin, vimentin, and Snail. We also found that DIF-1 suppressed the expression levels of TAZ/YAP target gene products and EMT-related protein. Further, overexpression of TAZ and YAP attenuated the inhibitory effects of DIF-1 on these protein expressions. Migration and trans-well invasion assays revealed that DIF-1 significantly inhibited HeLa cell migration and invasion. DIF-1-induced proteasomal- and GSK-3-dependent degradation of TAZ and YAP proteins and inhibition of cell migration and invasion were also observed in human colon cancer cell line HCT-116. These results suggest that DIF-1 inhibits the TAZ/YAP signaling pathway via GSK-3 activation. Further, it has been suggested that the inhibition of EMT induced by DIF-1 is involved with the suppression of TAZ/YAP signaling pathway.
•We investigated the effect of DIF-1 on TAZ/YAP signaling pathway.•DIF-1 induced GSK-3-dependent proteasomal degradation of TAZ and YAP in HeLa and HCT-116 cells.•DIF-1 inhibited the expression of TAZ/YAP target gene products and EMT-related proteins.•DIF-1 inhibited migration and invasion of HeLa and HCT-116 cells.•Therefore, we concluded DIF-1 inhibited EMT via degradation of TAZ and YAP. |
| doi_str_mv | 10.1016/j.ejphar.2024.177184 |
| format | Article |
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•We investigated the effect of DIF-1 on TAZ/YAP signaling pathway.•DIF-1 induced GSK-3-dependent proteasomal degradation of TAZ and YAP in HeLa and HCT-116 cells.•DIF-1 inhibited the expression of TAZ/YAP target gene products and EMT-related proteins.•DIF-1 inhibited migration and invasion of HeLa and HCT-116 cells.•Therefore, we concluded DIF-1 inhibited EMT via degradation of TAZ and YAP.</description><identifier>ISSN: 0014-2999</identifier><identifier>ISSN: 1879-0712</identifier><identifier>EISSN: 1879-0712</identifier><identifier>DOI: 10.1016/j.ejphar.2024.177184</identifier><identifier>PMID: 39645220</identifier><language>eng</language><publisher>Netherlands: Elsevier B.V</publisher><subject>Acyltransferases ; Adaptor Proteins, Signal Transducing - genetics ; Adaptor Proteins, Signal Transducing - metabolism ; Cell Line, Tumor ; Cell Movement - drug effects ; Colonic Neoplasms - metabolism ; Colonic Neoplasms - pathology ; DIF-1 ; EMT ; Epithelial-Mesenchymal Transition - drug effects ; Female ; Gene Expression Regulation, Neoplastic - drug effects ; Glycogen Synthase Kinase 3 - metabolism ; GSK-3 ; HeLa Cells ; Humans ; Phosphoproteins - metabolism ; Proteasome Endopeptidase Complex - metabolism ; Proteolysis - drug effects ; Signal Transduction - drug effects ; TAZ/YAP signaling pathway ; Trans-Activators - genetics ; Trans-Activators - metabolism ; Transcription Factors - genetics ; Transcription Factors - metabolism ; Transcriptional Coactivator with PDZ-Binding Motif Proteins ; Uterine Cervical Neoplasms - metabolism ; Uterine Cervical Neoplasms - pathology ; YAP-Signaling Proteins - metabolism</subject><ispartof>European journal of pharmacology, 2025-01, Vol.987, p.177184, Article 177184</ispartof><rights>2024 Elsevier B.V.</rights><rights>Copyright © 2024 Elsevier B.V. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c241t-49a145fe63b09ead34faaca7c317bdc4d7eacc994801fce1cc9d8021c69f5683</cites><orcidid>0009-0000-1960-8268 ; 0000-0001-7722-0843</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0014299924008744$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3536,27903,27904,65309</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39645220$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Arioka, Masaki</creatorcontrib><creatorcontrib>Yi, Wang</creatorcontrib><creatorcontrib>Igawa, Kazunobu</creatorcontrib><creatorcontrib>Ishikane, Shin</creatorcontrib><creatorcontrib>Takahashi-Yanaga, Fumi</creatorcontrib><title>Differentiation-inducing factor-1 inhibits EMT by proteasomal degradation of TAZ and YAP in cervical and colon cancer cell lines</title><title>European journal of pharmacology</title><addtitle>Eur J Pharmacol</addtitle><description>We previously reported differentiation-inducing factor-1 (DIF-1) activated glycogen synthase kinase-3 (GSK-3) in various mammalian cells. GSK-3 has been proposed to regulate a number of signaling pathway including TAZ/YAP signaling pathway. To clarify the effect of DIF-1 on TAZ/YAP signaling pathway, we examined whether DIF-1 affect the expression levels of TAZ and YAP. We found that DIF-1-induced proteasomal- and GSK-3-dependent degradation of both TAZ and YAP in human cervical cancer cell line HeLa in a time- and dose-dependent manner. As TAZ/YAP signaling pathway is well known to accelerate the epithelial-mesenchymal transition (EMT) of the cancer cell, we examined the effect of TAZ/YAP signaling pathway on EMT-related proteins. Knockdown of TAZ and YAP proteins by siRNA significantly reduced the expression of fibronectin, vimentin, and Snail. We also found that DIF-1 suppressed the expression levels of TAZ/YAP target gene products and EMT-related protein. Further, overexpression of TAZ and YAP attenuated the inhibitory effects of DIF-1 on these protein expressions. Migration and trans-well invasion assays revealed that DIF-1 significantly inhibited HeLa cell migration and invasion. DIF-1-induced proteasomal- and GSK-3-dependent degradation of TAZ and YAP proteins and inhibition of cell migration and invasion were also observed in human colon cancer cell line HCT-116. These results suggest that DIF-1 inhibits the TAZ/YAP signaling pathway via GSK-3 activation. Further, it has been suggested that the inhibition of EMT induced by DIF-1 is involved with the suppression of TAZ/YAP signaling pathway.
•We investigated the effect of DIF-1 on TAZ/YAP signaling pathway.•DIF-1 induced GSK-3-dependent proteasomal degradation of TAZ and YAP in HeLa and HCT-116 cells.•DIF-1 inhibited the expression of TAZ/YAP target gene products and EMT-related proteins.•DIF-1 inhibited migration and invasion of HeLa and HCT-116 cells.•Therefore, we concluded DIF-1 inhibited EMT via degradation of TAZ and YAP.</description><subject>Acyltransferases</subject><subject>Adaptor Proteins, Signal Transducing - genetics</subject><subject>Adaptor Proteins, Signal Transducing - metabolism</subject><subject>Cell Line, Tumor</subject><subject>Cell Movement - drug effects</subject><subject>Colonic Neoplasms - metabolism</subject><subject>Colonic Neoplasms - pathology</subject><subject>DIF-1</subject><subject>EMT</subject><subject>Epithelial-Mesenchymal Transition - drug effects</subject><subject>Female</subject><subject>Gene Expression Regulation, Neoplastic - drug effects</subject><subject>Glycogen Synthase Kinase 3 - metabolism</subject><subject>GSK-3</subject><subject>HeLa Cells</subject><subject>Humans</subject><subject>Phosphoproteins - metabolism</subject><subject>Proteasome Endopeptidase Complex - metabolism</subject><subject>Proteolysis - drug effects</subject><subject>Signal Transduction - drug effects</subject><subject>TAZ/YAP signaling pathway</subject><subject>Trans-Activators - genetics</subject><subject>Trans-Activators - metabolism</subject><subject>Transcription Factors - genetics</subject><subject>Transcription Factors - metabolism</subject><subject>Transcriptional Coactivator with PDZ-Binding Motif Proteins</subject><subject>Uterine Cervical Neoplasms - metabolism</subject><subject>Uterine Cervical Neoplasms - pathology</subject><subject>YAP-Signaling Proteins - metabolism</subject><issn>0014-2999</issn><issn>1879-0712</issn><issn>1879-0712</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2025</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kD1vHCEQhlGUKL7Y-QeRRZlmz8CyHzSWTv6KJUdJcY3TIHYYbE57cIY9S-7y08Nl7ZSpQDPPywwPIV84W3LG27PNEje7R5OWggm55F3He_mOLHjfqYp1XLwnC8a4rIRS6oh8ynnDGGuUaD6So1q1shGCLcjvS-8cJgyTN5OPofLB7sGHB-oMTDFVnPrw6Ac_ZXr1fU2HF7pLcUKT49aM1OJDMvZvkkZH16tf1ARL71c_S4wCpmcPBTvUII4FAhNKtXTGkY4-YD4hH5wZM35-PY_J-vpqffGtuvtxc3uxuqtASD5VUhkuG4dtPTCFxtbSGQOmg5p3gwVpOzQASsmecQfIy932THBolWvavj4mX-dny_ZPe8yT3vp82MIEjPusay7bwnW9KqicUUgx54RO75LfmvSiOdMH9XqjZ_X6oF7P6kvs9HXCftii_Rd6c12A8xnA8s1nj0ln8Fh0WJ8QJm2j__-EPyjSmEk</recordid><startdate>20250115</startdate><enddate>20250115</enddate><creator>Arioka, Masaki</creator><creator>Yi, Wang</creator><creator>Igawa, Kazunobu</creator><creator>Ishikane, Shin</creator><creator>Takahashi-Yanaga, Fumi</creator><general>Elsevier B.V</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>7X8</scope><orcidid>https://orcid.org/0009-0000-1960-8268</orcidid><orcidid>https://orcid.org/0000-0001-7722-0843</orcidid></search><sort><creationdate>20250115</creationdate><title>Differentiation-inducing factor-1 inhibits EMT by proteasomal degradation of TAZ and YAP in cervical and colon cancer cell lines</title><author>Arioka, Masaki ; Yi, Wang ; Igawa, Kazunobu ; Ishikane, Shin ; Takahashi-Yanaga, Fumi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c241t-49a145fe63b09ead34faaca7c317bdc4d7eacc994801fce1cc9d8021c69f5683</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2025</creationdate><topic>Acyltransferases</topic><topic>Adaptor Proteins, Signal Transducing - genetics</topic><topic>Adaptor Proteins, Signal Transducing - metabolism</topic><topic>Cell Line, Tumor</topic><topic>Cell Movement - drug effects</topic><topic>Colonic Neoplasms - metabolism</topic><topic>Colonic Neoplasms - pathology</topic><topic>DIF-1</topic><topic>EMT</topic><topic>Epithelial-Mesenchymal Transition - drug effects</topic><topic>Female</topic><topic>Gene Expression Regulation, Neoplastic - drug effects</topic><topic>Glycogen Synthase Kinase 3 - metabolism</topic><topic>GSK-3</topic><topic>HeLa Cells</topic><topic>Humans</topic><topic>Phosphoproteins - metabolism</topic><topic>Proteasome Endopeptidase Complex - metabolism</topic><topic>Proteolysis - drug effects</topic><topic>Signal Transduction - drug effects</topic><topic>TAZ/YAP signaling pathway</topic><topic>Trans-Activators - genetics</topic><topic>Trans-Activators - metabolism</topic><topic>Transcription Factors - genetics</topic><topic>Transcription Factors - metabolism</topic><topic>Transcriptional Coactivator with PDZ-Binding Motif Proteins</topic><topic>Uterine Cervical Neoplasms - metabolism</topic><topic>Uterine Cervical Neoplasms - pathology</topic><topic>YAP-Signaling Proteins - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Arioka, Masaki</creatorcontrib><creatorcontrib>Yi, Wang</creatorcontrib><creatorcontrib>Igawa, Kazunobu</creatorcontrib><creatorcontrib>Ishikane, Shin</creatorcontrib><creatorcontrib>Takahashi-Yanaga, Fumi</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>European journal of pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Arioka, Masaki</au><au>Yi, Wang</au><au>Igawa, Kazunobu</au><au>Ishikane, Shin</au><au>Takahashi-Yanaga, Fumi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Differentiation-inducing factor-1 inhibits EMT by proteasomal degradation of TAZ and YAP in cervical and colon cancer cell lines</atitle><jtitle>European journal of pharmacology</jtitle><addtitle>Eur J Pharmacol</addtitle><date>2025-01-15</date><risdate>2025</risdate><volume>987</volume><spage>177184</spage><pages>177184-</pages><artnum>177184</artnum><issn>0014-2999</issn><issn>1879-0712</issn><eissn>1879-0712</eissn><abstract>We previously reported differentiation-inducing factor-1 (DIF-1) activated glycogen synthase kinase-3 (GSK-3) in various mammalian cells. GSK-3 has been proposed to regulate a number of signaling pathway including TAZ/YAP signaling pathway. To clarify the effect of DIF-1 on TAZ/YAP signaling pathway, we examined whether DIF-1 affect the expression levels of TAZ and YAP. We found that DIF-1-induced proteasomal- and GSK-3-dependent degradation of both TAZ and YAP in human cervical cancer cell line HeLa in a time- and dose-dependent manner. As TAZ/YAP signaling pathway is well known to accelerate the epithelial-mesenchymal transition (EMT) of the cancer cell, we examined the effect of TAZ/YAP signaling pathway on EMT-related proteins. Knockdown of TAZ and YAP proteins by siRNA significantly reduced the expression of fibronectin, vimentin, and Snail. We also found that DIF-1 suppressed the expression levels of TAZ/YAP target gene products and EMT-related protein. Further, overexpression of TAZ and YAP attenuated the inhibitory effects of DIF-1 on these protein expressions. Migration and trans-well invasion assays revealed that DIF-1 significantly inhibited HeLa cell migration and invasion. DIF-1-induced proteasomal- and GSK-3-dependent degradation of TAZ and YAP proteins and inhibition of cell migration and invasion were also observed in human colon cancer cell line HCT-116. These results suggest that DIF-1 inhibits the TAZ/YAP signaling pathway via GSK-3 activation. Further, it has been suggested that the inhibition of EMT induced by DIF-1 is involved with the suppression of TAZ/YAP signaling pathway.
•We investigated the effect of DIF-1 on TAZ/YAP signaling pathway.•DIF-1 induced GSK-3-dependent proteasomal degradation of TAZ and YAP in HeLa and HCT-116 cells.•DIF-1 inhibited the expression of TAZ/YAP target gene products and EMT-related proteins.•DIF-1 inhibited migration and invasion of HeLa and HCT-116 cells.•Therefore, we concluded DIF-1 inhibited EMT via degradation of TAZ and YAP.</abstract><cop>Netherlands</cop><pub>Elsevier B.V</pub><pmid>39645220</pmid><doi>10.1016/j.ejphar.2024.177184</doi><orcidid>https://orcid.org/0009-0000-1960-8268</orcidid><orcidid>https://orcid.org/0000-0001-7722-0843</orcidid></addata></record> |
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| subjects | Acyltransferases Adaptor Proteins, Signal Transducing - genetics Adaptor Proteins, Signal Transducing - metabolism Cell Line, Tumor Cell Movement - drug effects Colonic Neoplasms - metabolism Colonic Neoplasms - pathology DIF-1 EMT Epithelial-Mesenchymal Transition - drug effects Female Gene Expression Regulation, Neoplastic - drug effects Glycogen Synthase Kinase 3 - metabolism GSK-3 HeLa Cells Humans Phosphoproteins - metabolism Proteasome Endopeptidase Complex - metabolism Proteolysis - drug effects Signal Transduction - drug effects TAZ/YAP signaling pathway Trans-Activators - genetics Trans-Activators - metabolism Transcription Factors - genetics Transcription Factors - metabolism Transcriptional Coactivator with PDZ-Binding Motif Proteins Uterine Cervical Neoplasms - metabolism Uterine Cervical Neoplasms - pathology YAP-Signaling Proteins - metabolism |
| title | Differentiation-inducing factor-1 inhibits EMT by proteasomal degradation of TAZ and YAP in cervical and colon cancer cell lines |
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