A new role of GRP75-USP1-SIX1 protein complex in driving prostate cancer progression and castration resistance
Prostate cancer (PC) is the second most common cancer with limited treatment option in males. Although the reactivation of embryonic signals in adult cells is one of the characteristics of cancer, the underlying protein degradation mechanism remains elusive. Here, we show that the molecular chaperon...
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| Veröffentlicht in: | Oncogene 2021-06, Vol.40 (25), p.4291-4306 |
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| creator | Liao, Yuning Liu, Yuan Shao, Zhenlong Xia, Xiaohong Deng, Yuanfei Cai, Jianyu Yao, Leyi He, Jinchan Yu, Cuifu Hu, Tumei Sun, Wenshuang Liu, Fang Tang, Daolin Liu, Jinbao Huang, Hongbiao |
| description | Prostate cancer (PC) is the second most common cancer with limited treatment option in males. Although the reactivation of embryonic signals in adult cells is one of the characteristics of cancer, the underlying protein degradation mechanism remains elusive. Here, we show that the molecular chaperone GRP75 is a key player in PC cells by maintaining the protein stability of SIX1, a transcription factor for embryonic development. Mechanistically, GRP75 provides a platform to recruit the deubiquitinating enzyme USP1 to inhibit K48-linked polyubiquitination of SIX1. Structurally, the C-terminus of GRP75 (433-679 aa) contains a peptide binding domain, which is required for the formation of GRP75-USP1-SIX1 protein complex. Functionally, pharmacological or genetic inhibition of the GRP75-USP1-SIX1 protein complex suppresses tumor growth and overcomes the castration resistance of PC cells in vitro and in xenograft mouse models. Clinically, the protein expression of SIX1 in PC tumor tissues is positively correlated with the expression of GRP75 and USP1. These new findings not only enhance our understanding of the protein degradation mechanism, but also may provide a potential way to enhance the anti-cancer activity of androgen suppression therapy. |
| doi_str_mv | 10.1038/s41388-021-01851-0 |
| format | Article |
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Although the reactivation of embryonic signals in adult cells is one of the characteristics of cancer, the underlying protein degradation mechanism remains elusive. Here, we show that the molecular chaperone GRP75 is a key player in PC cells by maintaining the protein stability of SIX1, a transcription factor for embryonic development. Mechanistically, GRP75 provides a platform to recruit the deubiquitinating enzyme USP1 to inhibit K48-linked polyubiquitination of SIX1. Structurally, the C-terminus of GRP75 (433-679 aa) contains a peptide binding domain, which is required for the formation of GRP75-USP1-SIX1 protein complex. Functionally, pharmacological or genetic inhibition of the GRP75-USP1-SIX1 protein complex suppresses tumor growth and overcomes the castration resistance of PC cells in vitro and in xenograft mouse models. Clinically, the protein expression of SIX1 in PC tumor tissues is positively correlated with the expression of GRP75 and USP1. These new findings not only enhance our understanding of the protein degradation mechanism, but also may provide a potential way to enhance the anti-cancer activity of androgen suppression therapy.</description><identifier>ISSN: 0950-9232</identifier><identifier>EISSN: 1476-5594</identifier><identifier>DOI: 10.1038/s41388-021-01851-0</identifier><identifier>PMID: 34079090</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/1 ; 13/2 ; 13/31 ; 13/51 ; 13/89 ; 14/35 ; 42/109 ; 631/67/1059/602 ; 631/67/589/466 ; 82/80 ; Animal models ; Animals ; Antitumor activity ; Apoptosis ; C-Terminus ; Castration ; Cell Biology ; Cell Line, Tumor ; Cell Proliferation - genetics ; Development and progression ; Disease Progression ; Drug resistance ; Embryogenesis ; Gene Expression Regulation, Neoplastic - genetics ; Genetic aspects ; Health aspects ; HEK293 Cells ; Homeodomain Proteins - genetics ; HSP70 Heat-Shock Proteins - genetics ; Human Genetics ; Humans ; Internal Medicine ; Male ; Medicine ; Medicine & Public Health ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Mitochondrial Proteins - genetics ; Oncology ; PC-3 Cells ; Pheochromocytoma cells ; Prostate - pathology ; Prostate cancer ; Prostatic Neoplasms, Castration-Resistant - genetics ; Prostatic Neoplasms, Castration-Resistant - pathology ; Proteins ; Proteolysis ; Receptors, Androgen - genetics ; Signal Transduction - genetics ; SIX gene family ; Transcription factors ; Transcription Factors - genetics ; Ubiquitin-Specific Proteases - genetics ; Ubiquitination - genetics ; Xenografts</subject><ispartof>Oncogene, 2021-06, Vol.40 (25), p.4291-4306</ispartof><rights>The Author(s), under exclusive licence to Springer Nature Limited 2021</rights><rights>COPYRIGHT 2021 Nature Publishing Group</rights><rights>The Author(s), under exclusive licence to Springer Nature Limited 2021.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c442t-c30017d408cf31cf8a1af3ae9d06ead7cd57efc8ef1fc80665b465d0cbaa3eb03</citedby><cites>FETCH-LOGICAL-c442t-c30017d408cf31cf8a1af3ae9d06ead7cd57efc8ef1fc80665b465d0cbaa3eb03</cites><orcidid>0000-0003-0343-1933 ; 0000-0002-1903-6180 ; 0000-0002-9873-0559 ; 0000-0003-2220-2407</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/s41388-021-01851-0$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41388-021-01851-0$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34079090$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Liao, Yuning</creatorcontrib><creatorcontrib>Liu, Yuan</creatorcontrib><creatorcontrib>Shao, Zhenlong</creatorcontrib><creatorcontrib>Xia, Xiaohong</creatorcontrib><creatorcontrib>Deng, Yuanfei</creatorcontrib><creatorcontrib>Cai, Jianyu</creatorcontrib><creatorcontrib>Yao, Leyi</creatorcontrib><creatorcontrib>He, Jinchan</creatorcontrib><creatorcontrib>Yu, Cuifu</creatorcontrib><creatorcontrib>Hu, Tumei</creatorcontrib><creatorcontrib>Sun, Wenshuang</creatorcontrib><creatorcontrib>Liu, Fang</creatorcontrib><creatorcontrib>Tang, Daolin</creatorcontrib><creatorcontrib>Liu, Jinbao</creatorcontrib><creatorcontrib>Huang, Hongbiao</creatorcontrib><title>A new role of GRP75-USP1-SIX1 protein complex in driving prostate cancer progression and castration resistance</title><title>Oncogene</title><addtitle>Oncogene</addtitle><addtitle>Oncogene</addtitle><description>Prostate cancer (PC) is the second most common cancer with limited treatment option in males. Although the reactivation of embryonic signals in adult cells is one of the characteristics of cancer, the underlying protein degradation mechanism remains elusive. Here, we show that the molecular chaperone GRP75 is a key player in PC cells by maintaining the protein stability of SIX1, a transcription factor for embryonic development. Mechanistically, GRP75 provides a platform to recruit the deubiquitinating enzyme USP1 to inhibit K48-linked polyubiquitination of SIX1. Structurally, the C-terminus of GRP75 (433-679 aa) contains a peptide binding domain, which is required for the formation of GRP75-USP1-SIX1 protein complex. Functionally, pharmacological or genetic inhibition of the GRP75-USP1-SIX1 protein complex suppresses tumor growth and overcomes the castration resistance of PC cells in vitro and in xenograft mouse models. Clinically, the protein expression of SIX1 in PC tumor tissues is positively correlated with the expression of GRP75 and USP1. 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Although the reactivation of embryonic signals in adult cells is one of the characteristics of cancer, the underlying protein degradation mechanism remains elusive. Here, we show that the molecular chaperone GRP75 is a key player in PC cells by maintaining the protein stability of SIX1, a transcription factor for embryonic development. Mechanistically, GRP75 provides a platform to recruit the deubiquitinating enzyme USP1 to inhibit K48-linked polyubiquitination of SIX1. Structurally, the C-terminus of GRP75 (433-679 aa) contains a peptide binding domain, which is required for the formation of GRP75-USP1-SIX1 protein complex. Functionally, pharmacological or genetic inhibition of the GRP75-USP1-SIX1 protein complex suppresses tumor growth and overcomes the castration resistance of PC cells in vitro and in xenograft mouse models. Clinically, the protein expression of SIX1 in PC tumor tissues is positively correlated with the expression of GRP75 and USP1. These new findings not only enhance our understanding of the protein degradation mechanism, but also may provide a potential way to enhance the anti-cancer activity of androgen suppression therapy.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>34079090</pmid><doi>10.1038/s41388-021-01851-0</doi><tpages>16</tpages><orcidid>https://orcid.org/0000-0003-0343-1933</orcidid><orcidid>https://orcid.org/0000-0002-1903-6180</orcidid><orcidid>https://orcid.org/0000-0002-9873-0559</orcidid><orcidid>https://orcid.org/0000-0003-2220-2407</orcidid></addata></record> |
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| ispartof | Oncogene, 2021-06, Vol.40 (25), p.4291-4306 |
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| subjects | 13/1 13/2 13/31 13/51 13/89 14/35 42/109 631/67/1059/602 631/67/589/466 82/80 Animal models Animals Antitumor activity Apoptosis C-Terminus Castration Cell Biology Cell Line, Tumor Cell Proliferation - genetics Development and progression Disease Progression Drug resistance Embryogenesis Gene Expression Regulation, Neoplastic - genetics Genetic aspects Health aspects HEK293 Cells Homeodomain Proteins - genetics HSP70 Heat-Shock Proteins - genetics Human Genetics Humans Internal Medicine Male Medicine Medicine & Public Health Mice Mice, Inbred BALB C Mice, Nude Mitochondrial Proteins - genetics Oncology PC-3 Cells Pheochromocytoma cells Prostate - pathology Prostate cancer Prostatic Neoplasms, Castration-Resistant - genetics Prostatic Neoplasms, Castration-Resistant - pathology Proteins Proteolysis Receptors, Androgen - genetics Signal Transduction - genetics SIX gene family Transcription factors Transcription Factors - genetics Ubiquitin-Specific Proteases - genetics Ubiquitination - genetics Xenografts |
| title | A new role of GRP75-USP1-SIX1 protein complex in driving prostate cancer progression and castration resistance |
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