DAB2IP suppresses tumor malignancy by inhibiting GRP75-driven p53 ubiquitination in colon cancer
Increasing evidence has shown that DAB2IP acts as a tumor suppressor and plays an inhibitory role in many signals associated with tumorigenesis. However, the underlying mechanism of this function remains unclear. Our study shows that DAB2IP was positively associated with a good prognosis in patients...
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| Veröffentlicht in: | Cancer letters 2022-04, Vol.532, p.215588-215588, Article 215588 |
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| container_title | Cancer letters |
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| creator | Feng, Shengjie Huang, Qingwen Deng, Jiao Jia, Weiyi Gong, Jianping Xie, Daxing Shen, Jie Liu, Liang |
| description | Increasing evidence has shown that DAB2IP acts as a tumor suppressor and plays an inhibitory role in many signals associated with tumorigenesis. However, the underlying mechanism of this function remains unclear. Our study shows that DAB2IP was positively associated with a good prognosis in patients with colorectal cancer and wild-type p53 expression. An in vitro assay showed that DAB2IP elicited potent tumor-suppressive effects by inhibiting cell invasiveness and colony formation and promoting cell apoptosis in wild-type p53 colon cancer cells. In addition, DAB2IP improved the stability of wild-type p53 by inhibiting its degradation in a ubiquitin-proteasome-dependent manner. Using mass spectrometry profiling, we revealed that DAB2IP and p53 interacted with the ubiquitin ligase-related protein GRP75. Mechanistically, DAB2IP is competitively bound to GRP75, thus reducing GRP75-driven p53 ubiquitination and degradation. Moreover, the Ras-GAP domain was required for the DAB2IP-GRP75 interaction and DAB2IP-mediated p53 ubiquitination. Finally, animal experiments revealed that DAB2IP inhibited tumor progression in vivo. In conclusion, our study presents a novel function of DAB2IP in GRP75-driven wild-type p53 degradation, providing new insight into DAB2IP-induced tumor suppression and a novel molecular interpretation of the p53 pathway.
•DAB2IP expression correlates with better prognosis in colorectal cancers with WT p53.•DAB2IP prolongs the half-life of wild-type p53 and activates p53 signaling.•DAB2IP inhibits p53 ubiquitination by competitively antagonizing the GRP75 protein.•DAB2IP regulates p53 by interacting with GRP75 via the Ras-GAP domain. |
| doi_str_mv | 10.1016/j.canlet.2022.215588 |
| format | Article |
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•DAB2IP expression correlates with better prognosis in colorectal cancers with WT p53.•DAB2IP prolongs the half-life of wild-type p53 and activates p53 signaling.•DAB2IP inhibits p53 ubiquitination by competitively antagonizing the GRP75 protein.•DAB2IP regulates p53 by interacting with GRP75 via the Ras-GAP domain.</description><identifier>ISSN: 0304-3835</identifier><identifier>EISSN: 1872-7980</identifier><identifier>DOI: 10.1016/j.canlet.2022.215588</identifier><identifier>PMID: 35150809</identifier><language>eng</language><publisher>Ireland: Elsevier B.V</publisher><subject>Animal research ; Animals ; Antibodies ; Antigens ; Apoptosis ; ASK1-Interacting protein ; Cell cycle ; Cell Line, Tumor ; Cell Proliferation ; Colon cancer ; Colonic Neoplasms - drug therapy ; Colonic Neoplasms - genetics ; Colorectal cancer ; Colorectal carcinoma ; Competitive antagonism ; Degradation ; Epigenetics ; Fluorides ; HSP70 Heat-Shock Proteins ; Humans ; Invasiveness ; Malignancy ; Mass spectroscopy ; Membrane Proteins ; Mortalin ; Mutagenesis ; Mutation ; p53 degradation ; p53 Protein ; Plasmids ; Proteasomes ; Proteins ; ras GTPase-Activating Proteins - genetics ; ras GTPase-Activating Proteins - metabolism ; Ras-GAP domain ; Senescence ; Tumor suppressor genes ; Tumor Suppressor Protein p53 - genetics ; Tumor Suppressor Protein p53 - metabolism ; Tumorigenesis ; Tumors ; Ubiquitin ; Ubiquitin - metabolism ; Ubiquitin-protein ligase ; Ubiquitination</subject><ispartof>Cancer letters, 2022-04, Vol.532, p.215588-215588, Article 215588</ispartof><rights>2022 The Authors</rights><rights>Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.</rights><rights>2022. The Authors</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c436t-cdb4b366b57a8c5010029cf35c9f5cb1905525d93a2aa3436e529f98d7fd13443</citedby><cites>FETCH-LOGICAL-c436t-cdb4b366b57a8c5010029cf35c9f5cb1905525d93a2aa3436e529f98d7fd13443</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.canlet.2022.215588$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,780,784,3548,27922,27923,45993</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35150809$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Feng, Shengjie</creatorcontrib><creatorcontrib>Huang, Qingwen</creatorcontrib><creatorcontrib>Deng, Jiao</creatorcontrib><creatorcontrib>Jia, Weiyi</creatorcontrib><creatorcontrib>Gong, Jianping</creatorcontrib><creatorcontrib>Xie, Daxing</creatorcontrib><creatorcontrib>Shen, Jie</creatorcontrib><creatorcontrib>Liu, Liang</creatorcontrib><title>DAB2IP suppresses tumor malignancy by inhibiting GRP75-driven p53 ubiquitination in colon cancer</title><title>Cancer letters</title><addtitle>Cancer Lett</addtitle><description>Increasing evidence has shown that DAB2IP acts as a tumor suppressor and plays an inhibitory role in many signals associated with tumorigenesis. However, the underlying mechanism of this function remains unclear. Our study shows that DAB2IP was positively associated with a good prognosis in patients with colorectal cancer and wild-type p53 expression. An in vitro assay showed that DAB2IP elicited potent tumor-suppressive effects by inhibiting cell invasiveness and colony formation and promoting cell apoptosis in wild-type p53 colon cancer cells. In addition, DAB2IP improved the stability of wild-type p53 by inhibiting its degradation in a ubiquitin-proteasome-dependent manner. Using mass spectrometry profiling, we revealed that DAB2IP and p53 interacted with the ubiquitin ligase-related protein GRP75. Mechanistically, DAB2IP is competitively bound to GRP75, thus reducing GRP75-driven p53 ubiquitination and degradation. Moreover, the Ras-GAP domain was required for the DAB2IP-GRP75 interaction and DAB2IP-mediated p53 ubiquitination. Finally, animal experiments revealed that DAB2IP inhibited tumor progression in vivo. In conclusion, our study presents a novel function of DAB2IP in GRP75-driven wild-type p53 degradation, providing new insight into DAB2IP-induced tumor suppression and a novel molecular interpretation of the p53 pathway.
•DAB2IP expression correlates with better prognosis in colorectal cancers with WT p53.•DAB2IP prolongs the half-life of wild-type p53 and activates p53 signaling.•DAB2IP inhibits p53 ubiquitination by competitively antagonizing the GRP75 protein.•DAB2IP regulates p53 by interacting with GRP75 via the Ras-GAP domain.</description><subject>Animal research</subject><subject>Animals</subject><subject>Antibodies</subject><subject>Antigens</subject><subject>Apoptosis</subject><subject>ASK1-Interacting protein</subject><subject>Cell cycle</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation</subject><subject>Colon cancer</subject><subject>Colonic Neoplasms - drug therapy</subject><subject>Colonic Neoplasms - genetics</subject><subject>Colorectal cancer</subject><subject>Colorectal carcinoma</subject><subject>Competitive antagonism</subject><subject>Degradation</subject><subject>Epigenetics</subject><subject>Fluorides</subject><subject>HSP70 Heat-Shock Proteins</subject><subject>Humans</subject><subject>Invasiveness</subject><subject>Malignancy</subject><subject>Mass spectroscopy</subject><subject>Membrane Proteins</subject><subject>Mortalin</subject><subject>Mutagenesis</subject><subject>Mutation</subject><subject>p53 degradation</subject><subject>p53 Protein</subject><subject>Plasmids</subject><subject>Proteasomes</subject><subject>Proteins</subject><subject>ras GTPase-Activating Proteins - genetics</subject><subject>ras GTPase-Activating Proteins - metabolism</subject><subject>Ras-GAP domain</subject><subject>Senescence</subject><subject>Tumor suppressor genes</subject><subject>Tumor Suppressor Protein p53 - genetics</subject><subject>Tumor Suppressor Protein p53 - metabolism</subject><subject>Tumorigenesis</subject><subject>Tumors</subject><subject>Ubiquitin</subject><subject>Ubiquitin - metabolism</subject><subject>Ubiquitin-protein ligase</subject><subject>Ubiquitination</subject><issn>0304-3835</issn><issn>1872-7980</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kU9v1DAQxS0EotvCN0DIEpdesh3bmcS-IPUPLZUqUSE4G8dxileJk9pJpf32eJXCgUNPM9L83szoPUI-MNgyYNXZbmtN6N285cD5ljNEKV-RDZM1L2ol4TXZgICyEFLgETlOaQcAWNb4lhwJZAgS1Ib8ujq_4Lf3NC3TFF1KLtF5GcZIB9P7h2CC3dNmT3347Rs_-_BAb77f11i00T-5QCcUdGn843KYmdmPIaPUjn1u8nvWxXfkTWf65N4_1xPy8_rLj8uvxd23m9vL87vClqKaC9s2ZSOqqsHaSIvAALiynUCrOrQNU4DIsVXCcGNEljjkqlOyrbuWibIUJ-R03TvF8XFxadaDT9b1vQluXJLmFZcCIEsz-uk_dDcuMeTvMiUqUTNUB6pcKRvHlKLr9BT9YOJeM9CHBPROrwnoQwJ6TSDLPj4vX5rBtf9Efy3PwOcVcNmNJ--iTta7bFXro7Ozbkf_8oU_ANeXKg</recordid><startdate>20220428</startdate><enddate>20220428</enddate><creator>Feng, Shengjie</creator><creator>Huang, Qingwen</creator><creator>Deng, Jiao</creator><creator>Jia, Weiyi</creator><creator>Gong, Jianping</creator><creator>Xie, Daxing</creator><creator>Shen, Jie</creator><creator>Liu, Liang</creator><general>Elsevier B.V</general><general>Elsevier Limited</general><scope>6I.</scope><scope>AAFTH</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>7TO</scope><scope>7U9</scope><scope>H94</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>7X8</scope></search><sort><creationdate>20220428</creationdate><title>DAB2IP suppresses tumor malignancy by inhibiting GRP75-driven p53 ubiquitination in colon cancer</title><author>Feng, Shengjie ; Huang, Qingwen ; Deng, Jiao ; Jia, Weiyi ; Gong, Jianping ; Xie, Daxing ; Shen, Jie ; Liu, Liang</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c436t-cdb4b366b57a8c5010029cf35c9f5cb1905525d93a2aa3436e529f98d7fd13443</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Animal research</topic><topic>Animals</topic><topic>Antibodies</topic><topic>Antigens</topic><topic>Apoptosis</topic><topic>ASK1-Interacting protein</topic><topic>Cell cycle</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation</topic><topic>Colon cancer</topic><topic>Colonic Neoplasms - drug therapy</topic><topic>Colonic Neoplasms - genetics</topic><topic>Colorectal cancer</topic><topic>Colorectal carcinoma</topic><topic>Competitive antagonism</topic><topic>Degradation</topic><topic>Epigenetics</topic><topic>Fluorides</topic><topic>HSP70 Heat-Shock Proteins</topic><topic>Humans</topic><topic>Invasiveness</topic><topic>Malignancy</topic><topic>Mass spectroscopy</topic><topic>Membrane Proteins</topic><topic>Mortalin</topic><topic>Mutagenesis</topic><topic>Mutation</topic><topic>p53 degradation</topic><topic>p53 Protein</topic><topic>Plasmids</topic><topic>Proteasomes</topic><topic>Proteins</topic><topic>ras GTPase-Activating Proteins - genetics</topic><topic>ras GTPase-Activating Proteins - metabolism</topic><topic>Ras-GAP domain</topic><topic>Senescence</topic><topic>Tumor suppressor genes</topic><topic>Tumor Suppressor Protein p53 - genetics</topic><topic>Tumor Suppressor Protein p53 - metabolism</topic><topic>Tumorigenesis</topic><topic>Tumors</topic><topic>Ubiquitin</topic><topic>Ubiquitin - metabolism</topic><topic>Ubiquitin-protein ligase</topic><topic>Ubiquitination</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Feng, Shengjie</creatorcontrib><creatorcontrib>Huang, Qingwen</creatorcontrib><creatorcontrib>Deng, Jiao</creatorcontrib><creatorcontrib>Jia, Weiyi</creatorcontrib><creatorcontrib>Gong, Jianping</creatorcontrib><creatorcontrib>Xie, Daxing</creatorcontrib><creatorcontrib>Shen, Jie</creatorcontrib><creatorcontrib>Liu, Liang</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>MEDLINE - Academic</collection><jtitle>Cancer letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Feng, Shengjie</au><au>Huang, Qingwen</au><au>Deng, Jiao</au><au>Jia, Weiyi</au><au>Gong, Jianping</au><au>Xie, Daxing</au><au>Shen, Jie</au><au>Liu, Liang</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>DAB2IP suppresses tumor malignancy by inhibiting GRP75-driven p53 ubiquitination in colon cancer</atitle><jtitle>Cancer letters</jtitle><addtitle>Cancer Lett</addtitle><date>2022-04-28</date><risdate>2022</risdate><volume>532</volume><spage>215588</spage><epage>215588</epage><pages>215588-215588</pages><artnum>215588</artnum><issn>0304-3835</issn><eissn>1872-7980</eissn><abstract>Increasing evidence has shown that DAB2IP acts as a tumor suppressor and plays an inhibitory role in many signals associated with tumorigenesis. However, the underlying mechanism of this function remains unclear. Our study shows that DAB2IP was positively associated with a good prognosis in patients with colorectal cancer and wild-type p53 expression. An in vitro assay showed that DAB2IP elicited potent tumor-suppressive effects by inhibiting cell invasiveness and colony formation and promoting cell apoptosis in wild-type p53 colon cancer cells. In addition, DAB2IP improved the stability of wild-type p53 by inhibiting its degradation in a ubiquitin-proteasome-dependent manner. Using mass spectrometry profiling, we revealed that DAB2IP and p53 interacted with the ubiquitin ligase-related protein GRP75. Mechanistically, DAB2IP is competitively bound to GRP75, thus reducing GRP75-driven p53 ubiquitination and degradation. Moreover, the Ras-GAP domain was required for the DAB2IP-GRP75 interaction and DAB2IP-mediated p53 ubiquitination. Finally, animal experiments revealed that DAB2IP inhibited tumor progression in vivo. In conclusion, our study presents a novel function of DAB2IP in GRP75-driven wild-type p53 degradation, providing new insight into DAB2IP-induced tumor suppression and a novel molecular interpretation of the p53 pathway.
•DAB2IP expression correlates with better prognosis in colorectal cancers with WT p53.•DAB2IP prolongs the half-life of wild-type p53 and activates p53 signaling.•DAB2IP inhibits p53 ubiquitination by competitively antagonizing the GRP75 protein.•DAB2IP regulates p53 by interacting with GRP75 via the Ras-GAP domain.</abstract><cop>Ireland</cop><pub>Elsevier B.V</pub><pmid>35150809</pmid><doi>10.1016/j.canlet.2022.215588</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animal research Animals Antibodies Antigens Apoptosis ASK1-Interacting protein Cell cycle Cell Line, Tumor Cell Proliferation Colon cancer Colonic Neoplasms - drug therapy Colonic Neoplasms - genetics Colorectal cancer Colorectal carcinoma Competitive antagonism Degradation Epigenetics Fluorides HSP70 Heat-Shock Proteins Humans Invasiveness Malignancy Mass spectroscopy Membrane Proteins Mortalin Mutagenesis Mutation p53 degradation p53 Protein Plasmids Proteasomes Proteins ras GTPase-Activating Proteins - genetics ras GTPase-Activating Proteins - metabolism Ras-GAP domain Senescence Tumor suppressor genes Tumor Suppressor Protein p53 - genetics Tumor Suppressor Protein p53 - metabolism Tumorigenesis Tumors Ubiquitin Ubiquitin - metabolism Ubiquitin-protein ligase Ubiquitination |
| title | DAB2IP suppresses tumor malignancy by inhibiting GRP75-driven p53 ubiquitination in colon cancer |
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