Deubiquitylation and stabilization of Notch1 intracellular domain by ubiquitin-specific protease 8 enhance tumorigenesis in breast cancer
Notch, an essential factor in tissue development and homoeostasis, has been reported to play an oncogenic function in a variety of cancers. Here, we report ubiquitin-specific protease 8 (USP8) as a novel deubiquitylase of Notch1 intracellular domain (NICD). USP8 specifically stabilizes and deubiquit...
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| Veröffentlicht in: | Cell death and differentiation 2020-04, Vol.27 (4), p.1341-1354 |
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| creator | Shin, Soyeon Kim, Kyungeun Kim, Hwa-Ryeon Ylaya, Kris Do, Sung-Im Hewitt, Stephen M. Park, Hee-Sae Roe, Jae-Seok Chung, Joon-Yong Song, Jaewhan |
| description | Notch, an essential factor in tissue development and homoeostasis, has been reported to play an oncogenic function in a variety of cancers. Here, we report ubiquitin-specific protease 8 (USP8) as a novel deubiquitylase of Notch1 intracellular domain (NICD). USP8 specifically stabilizes and deubiquitylates NICD through a direct interaction. The inhibition of USP8 downregulated the Notch signalling pathway via NICD destabilization, resulting in the retardation of cellular growth, wound closure, and colony forming ability of breast cancer cell lines. These phenomena were restored by the reconstitution of NICD or USP8, supporting the direct interaction between these two proteins. The expression levels of NICD and USP8 proteins were positively correlated in patients with advanced breast cancer. Taken together, our results suggest that USP8 functions as a positive regulator of Notch signalling, offering a therapeutic target for breast cancer. |
| doi_str_mv | 10.1038/s41418-019-0419-1 |
| format | Article |
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Taken together, our results suggest that USP8 functions as a positive regulator of Notch signalling, offering a therapeutic target for breast cancer.</description><identifier>ISSN: 1350-9047</identifier><identifier>EISSN: 1476-5403</identifier><identifier>DOI: 10.1038/s41418-019-0419-1</identifier><identifier>PMID: 31527799</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13 ; 13/109 ; 13/31 ; 38 ; 38/91 ; 42 ; 45 ; 631/337/474/2289 ; 631/67/395 ; 631/80/474/582 ; 82 ; 82/51 ; Apoptosis ; Biochemistry ; Biomedical and Life Sciences ; Breast cancer ; Cell Biology ; Cell Cycle Analysis ; Intracellular ; Life Sciences ; Notch1 protein ; Signal transduction ; Stem Cells ; Therapeutic applications ; Therapeutic targets ; Tumor cell lines ; Tumorigenesis ; Ubiquitin ; Ubiquitin-specific proteinase</subject><ispartof>Cell death and differentiation, 2020-04, Vol.27 (4), p.1341-1354</ispartof><rights>The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare 2019</rights><rights>2019© The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare 2019</rights><rights>The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare 2019.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c498t-3265f21c62cab6162ca0c3e110b2e1438871a97339dbbc8e32602a9c388d79e63</citedby><cites>FETCH-LOGICAL-c498t-3265f21c62cab6162ca0c3e110b2e1438871a97339dbbc8e32602a9c388d79e63</cites><orcidid>0000-0001-8152-9210</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/PMC7206187/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7206187/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,41464,42533,51294,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31527799$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Shin, Soyeon</creatorcontrib><creatorcontrib>Kim, Kyungeun</creatorcontrib><creatorcontrib>Kim, Hwa-Ryeon</creatorcontrib><creatorcontrib>Ylaya, Kris</creatorcontrib><creatorcontrib>Do, Sung-Im</creatorcontrib><creatorcontrib>Hewitt, Stephen M.</creatorcontrib><creatorcontrib>Park, Hee-Sae</creatorcontrib><creatorcontrib>Roe, Jae-Seok</creatorcontrib><creatorcontrib>Chung, Joon-Yong</creatorcontrib><creatorcontrib>Song, Jaewhan</creatorcontrib><title>Deubiquitylation and stabilization of Notch1 intracellular domain by ubiquitin-specific protease 8 enhance tumorigenesis in breast cancer</title><title>Cell death and differentiation</title><addtitle>Cell Death Differ</addtitle><addtitle>Cell Death Differ</addtitle><description>Notch, an essential factor in tissue development and homoeostasis, has been reported to play an oncogenic function in a variety of cancers. Here, we report ubiquitin-specific protease 8 (USP8) as a novel deubiquitylase of Notch1 intracellular domain (NICD). USP8 specifically stabilizes and deubiquitylates NICD through a direct interaction. The inhibition of USP8 downregulated the Notch signalling pathway via NICD destabilization, resulting in the retardation of cellular growth, wound closure, and colony forming ability of breast cancer cell lines. These phenomena were restored by the reconstitution of NICD or USP8, supporting the direct interaction between these two proteins. The expression levels of NICD and USP8 proteins were positively correlated in patients with advanced breast cancer. 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ubiquitin-specific protease 8 enhance tumorigenesis in breast cancer</atitle><jtitle>Cell death and differentiation</jtitle><stitle>Cell Death Differ</stitle><addtitle>Cell Death Differ</addtitle><date>2020-04-01</date><risdate>2020</risdate><volume>27</volume><issue>4</issue><spage>1341</spage><epage>1354</epage><pages>1341-1354</pages><issn>1350-9047</issn><eissn>1476-5403</eissn><abstract>Notch, an essential factor in tissue development and homoeostasis, has been reported to play an oncogenic function in a variety of cancers. Here, we report ubiquitin-specific protease 8 (USP8) as a novel deubiquitylase of Notch1 intracellular domain (NICD). USP8 specifically stabilizes and deubiquitylates NICD through a direct interaction. The inhibition of USP8 downregulated the Notch signalling pathway via NICD destabilization, resulting in the retardation of cellular growth, wound closure, and colony forming ability of breast cancer cell lines. These phenomena were restored by the reconstitution of NICD or USP8, supporting the direct interaction between these two proteins. The expression levels of NICD and USP8 proteins were positively correlated in patients with advanced breast cancer. 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| subjects | 13 13/109 13/31 38 38/91 42 45 631/337/474/2289 631/67/395 631/80/474/582 82 82/51 Apoptosis Biochemistry Biomedical and Life Sciences Breast cancer Cell Biology Cell Cycle Analysis Intracellular Life Sciences Notch1 protein Signal transduction Stem Cells Therapeutic applications Therapeutic targets Tumor cell lines Tumorigenesis Ubiquitin Ubiquitin-specific proteinase |
| title | Deubiquitylation and stabilization of Notch1 intracellular domain by ubiquitin-specific protease 8 enhance tumorigenesis in breast cancer |
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