SKP2 promotes the metastasis of pancreatic ductal adenocarcinoma by suppressing TRIM21-mediated PSPC1 degradation

Despite significant advances in diagnostic techniques and treatment approaches, the prognosis of pancreatic ductal adenocarcinoma (PDAC) is still poor. Previous studies have reported that S-phase kinase-associated protein 2 (SKP2), a subunit of the SCF E3 ubiquitin ligase complex, is engaged in the...

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Veröffentlicht in:Cancer letters 2024-04, Vol.587, p.216733-216733, Article 216733
Hauptverfasser: Yuan, Jiahui, Zhu, Zeyao, Zhang, Pingping, Ashrafizadeh, Milad, Abd El-Aty, A.M., Hacımüftüoğlu, Ahmet, Linnebacher, Christina Susanne, Linnebacher, Michael, Sethi, Gautam, Gong, Peng, Zhang, Xianbin
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container_title Cancer letters
container_volume 587
creator Yuan, Jiahui
Zhu, Zeyao
Zhang, Pingping
Ashrafizadeh, Milad
Abd El-Aty, A.M.
Hacımüftüoğlu, Ahmet
Linnebacher, Christina Susanne
Linnebacher, Michael
Sethi, Gautam
Gong, Peng
Zhang, Xianbin
description Despite significant advances in diagnostic techniques and treatment approaches, the prognosis of pancreatic ductal adenocarcinoma (PDAC) is still poor. Previous studies have reported that S-phase kinase-associated protein 2 (SKP2), a subunit of the SCF E3 ubiquitin ligase complex, is engaged in the malignant biological behavior of some tumor entities. However, SKP2 has not been fully investigated in PDAC. In the present study, it was observed that high expression of SKP2 significantly correlates with decreased survival time. Further experiments suggested that SKP2 promotes metastasis by interacting with the putative transcription factor paraspeckle component 1 (PSPC1). According to the results of coimmunoprecipitation and ubiquitination assays, SKP2 depletion resulted in the polyubiquitination of PSPC1, followed by its degradation. Furthermore, the SKP2-mediated ubiquitination of PSPC1 partially depended on the activity of the E3 ligase TRIM21. In addition, inhibition of the SKP2/PSPC1 axis by SMIP004, a traditional inhibitor of SKP2, impaired the migration of PDAC cells. In summary, this study provides novel insight into the mechanisms involved in PDAC malignant progression. Targeting the SKP2/PSPC1 axis is a promising strategy for the treatment of PDAC. [Display omitted] •SKP2 is a promising prognostic indicator of pancreatic ductal adenocarcinoma.•SKP2 is able to ubiquitinate PSPC1 and promote the metastasis of PDAC cells.•SKP2-mediated ubiquitination of PSPC1 is partially dependent on TRIM21.•SMIP004 impairs PDAC cells migration through inhibiting the SKP2/PSPC1 axis.•Targeting SKP2/PSPC1 axis is an innovative strategy against PDAC.
doi_str_mv 10.1016/j.canlet.2024.216733
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Previous studies have reported that S-phase kinase-associated protein 2 (SKP2), a subunit of the SCF E3 ubiquitin ligase complex, is engaged in the malignant biological behavior of some tumor entities. However, SKP2 has not been fully investigated in PDAC. In the present study, it was observed that high expression of SKP2 significantly correlates with decreased survival time. Further experiments suggested that SKP2 promotes metastasis by interacting with the putative transcription factor paraspeckle component 1 (PSPC1). According to the results of coimmunoprecipitation and ubiquitination assays, SKP2 depletion resulted in the polyubiquitination of PSPC1, followed by its degradation. Furthermore, the SKP2-mediated ubiquitination of PSPC1 partially depended on the activity of the E3 ligase TRIM21. In addition, inhibition of the SKP2/PSPC1 axis by SMIP004, a traditional inhibitor of SKP2, impaired the migration of PDAC cells. In summary, this study provides novel insight into the mechanisms involved in PDAC malignant progression. Targeting the SKP2/PSPC1 axis is a promising strategy for the treatment of PDAC. [Display omitted] •SKP2 is a promising prognostic indicator of pancreatic ductal adenocarcinoma.•SKP2 is able to ubiquitinate PSPC1 and promote the metastasis of PDAC cells.•SKP2-mediated ubiquitination of PSPC1 is partially dependent on TRIM21.•SMIP004 impairs PDAC cells migration through inhibiting the SKP2/PSPC1 axis.•Targeting SKP2/PSPC1 axis is an innovative strategy against PDAC.</description><identifier>ISSN: 0304-3835</identifier><identifier>EISSN: 1872-7980</identifier><identifier>DOI: 10.1016/j.canlet.2024.216733</identifier><identifier>PMID: 38360141</identifier><language>eng</language><publisher>Ireland: Elsevier B.V</publisher><subject>Metastasis ; PDAC ; PSPC1 ; SKP2 ; Ubiquitin-mediated degradation</subject><ispartof>Cancer letters, 2024-04, Vol.587, p.216733-216733, Article 216733</ispartof><rights>2024 Elsevier B.V.</rights><rights>Copyright © 2024 Elsevier B.V. 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Previous studies have reported that S-phase kinase-associated protein 2 (SKP2), a subunit of the SCF E3 ubiquitin ligase complex, is engaged in the malignant biological behavior of some tumor entities. However, SKP2 has not been fully investigated in PDAC. In the present study, it was observed that high expression of SKP2 significantly correlates with decreased survival time. Further experiments suggested that SKP2 promotes metastasis by interacting with the putative transcription factor paraspeckle component 1 (PSPC1). According to the results of coimmunoprecipitation and ubiquitination assays, SKP2 depletion resulted in the polyubiquitination of PSPC1, followed by its degradation. Furthermore, the SKP2-mediated ubiquitination of PSPC1 partially depended on the activity of the E3 ligase TRIM21. In addition, inhibition of the SKP2/PSPC1 axis by SMIP004, a traditional inhibitor of SKP2, impaired the migration of PDAC cells. In summary, this study provides novel insight into the mechanisms involved in PDAC malignant progression. Targeting the SKP2/PSPC1 axis is a promising strategy for the treatment of PDAC. [Display omitted] •SKP2 is a promising prognostic indicator of pancreatic ductal adenocarcinoma.•SKP2 is able to ubiquitinate PSPC1 and promote the metastasis of PDAC cells.•SKP2-mediated ubiquitination of PSPC1 is partially dependent on TRIM21.•SMIP004 impairs PDAC cells migration through inhibiting the SKP2/PSPC1 axis.•Targeting SKP2/PSPC1 axis is an innovative strategy against PDAC.</description><subject>Metastasis</subject><subject>PDAC</subject><subject>PSPC1</subject><subject>SKP2</subject><subject>Ubiquitin-mediated degradation</subject><issn>0304-3835</issn><issn>1872-7980</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><recordid>eNp9kEtrHDEQhEVIsDeO_0EIOuYya71Go7kEwpKHsUMW2zmLXqnH0TIvS5qA_71lxskx0NDQVFVTHyHvOdtyxvXFcetg7DFvBRNqK7hupHxFNtw0ompaw16TDZNMVdLI-pS8TenIGKtVU5-Q03LTjCu-IQ-3V3tB5zgNU8ZE82-kA2ZIZUKiU0dnGF1EyMFRv7gMPQWP4-QgujBOA9DDI03LPEdMKYz39O7m8ofg1YA-QEZP97f7Hace7yP4kjKN78ibDvqE5y_7jPz6-uVu9726_vntcvf5unJSi1zVzCnZeKU7XbeItXGSNRKEM_WBaelBgxbATWnkW9NAp3XTubb2hnHBWi_PyMc1t5R7WDBlO4TksO9hxGlJVrTCCKWEaotUrVIXp5QidnaOYYD4aDmzz7Dt0a6w7TNsu8Iutg8vH5ZD6fvP9JduEXxaBVh6_gkYbXIBR1fYRHTZ-in8_8MTj3aRnA</recordid><startdate>20240410</startdate><enddate>20240410</enddate><creator>Yuan, Jiahui</creator><creator>Zhu, Zeyao</creator><creator>Zhang, Pingping</creator><creator>Ashrafizadeh, Milad</creator><creator>Abd El-Aty, A.M.</creator><creator>Hacımüftüoğlu, Ahmet</creator><creator>Linnebacher, Christina Susanne</creator><creator>Linnebacher, Michael</creator><creator>Sethi, Gautam</creator><creator>Gong, Peng</creator><creator>Zhang, Xianbin</creator><general>Elsevier B.V</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0001-6596-7907</orcidid><orcidid>https://orcid.org/0000-0002-8677-8475</orcidid><orcidid>https://orcid.org/0000-0001-6605-822X</orcidid><orcidid>https://orcid.org/0000-0001-8054-1402</orcidid></search><sort><creationdate>20240410</creationdate><title>SKP2 promotes the metastasis of pancreatic ductal adenocarcinoma by suppressing TRIM21-mediated PSPC1 degradation</title><author>Yuan, Jiahui ; Zhu, Zeyao ; Zhang, Pingping ; Ashrafizadeh, Milad ; Abd El-Aty, A.M. ; Hacımüftüoğlu, Ahmet ; Linnebacher, Christina Susanne ; Linnebacher, Michael ; Sethi, Gautam ; Gong, Peng ; Zhang, Xianbin</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c362t-50c437d46f659ee58c3073a2c85b063da6a62a18547d987af667fc95d801209d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Metastasis</topic><topic>PDAC</topic><topic>PSPC1</topic><topic>SKP2</topic><topic>Ubiquitin-mediated degradation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yuan, Jiahui</creatorcontrib><creatorcontrib>Zhu, Zeyao</creatorcontrib><creatorcontrib>Zhang, Pingping</creatorcontrib><creatorcontrib>Ashrafizadeh, Milad</creatorcontrib><creatorcontrib>Abd El-Aty, A.M.</creatorcontrib><creatorcontrib>Hacımüftüoğlu, Ahmet</creatorcontrib><creatorcontrib>Linnebacher, Christina Susanne</creatorcontrib><creatorcontrib>Linnebacher, Michael</creatorcontrib><creatorcontrib>Sethi, Gautam</creatorcontrib><creatorcontrib>Gong, Peng</creatorcontrib><creatorcontrib>Zhang, Xianbin</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Cancer letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yuan, Jiahui</au><au>Zhu, Zeyao</au><au>Zhang, Pingping</au><au>Ashrafizadeh, Milad</au><au>Abd El-Aty, A.M.</au><au>Hacımüftüoğlu, Ahmet</au><au>Linnebacher, Christina Susanne</au><au>Linnebacher, Michael</au><au>Sethi, Gautam</au><au>Gong, Peng</au><au>Zhang, Xianbin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>SKP2 promotes the metastasis of pancreatic ductal adenocarcinoma by suppressing TRIM21-mediated PSPC1 degradation</atitle><jtitle>Cancer letters</jtitle><addtitle>Cancer Lett</addtitle><date>2024-04-10</date><risdate>2024</risdate><volume>587</volume><spage>216733</spage><epage>216733</epage><pages>216733-216733</pages><artnum>216733</artnum><issn>0304-3835</issn><eissn>1872-7980</eissn><abstract>Despite significant advances in diagnostic techniques and treatment approaches, the prognosis of pancreatic ductal adenocarcinoma (PDAC) is still poor. Previous studies have reported that S-phase kinase-associated protein 2 (SKP2), a subunit of the SCF E3 ubiquitin ligase complex, is engaged in the malignant biological behavior of some tumor entities. However, SKP2 has not been fully investigated in PDAC. In the present study, it was observed that high expression of SKP2 significantly correlates with decreased survival time. Further experiments suggested that SKP2 promotes metastasis by interacting with the putative transcription factor paraspeckle component 1 (PSPC1). According to the results of coimmunoprecipitation and ubiquitination assays, SKP2 depletion resulted in the polyubiquitination of PSPC1, followed by its degradation. Furthermore, the SKP2-mediated ubiquitination of PSPC1 partially depended on the activity of the E3 ligase TRIM21. In addition, inhibition of the SKP2/PSPC1 axis by SMIP004, a traditional inhibitor of SKP2, impaired the migration of PDAC cells. 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source Elsevier ScienceDirect Journals Complete
subjects Metastasis
PDAC
PSPC1
SKP2
Ubiquitin-mediated degradation
title SKP2 promotes the metastasis of pancreatic ductal adenocarcinoma by suppressing TRIM21-mediated PSPC1 degradation
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