IDDF2023-ABS-0150 PRKAR2A interacts with EMSY to promote colitis-associated tumorigenesis
BackgroundIt has been reported that protein kinase cAMP-dependent type II regulatory subunit alpha (PRKAR2A) directly modulates some signaling pathways and is essential for colitis regulation, but its role in colitis-associated tumorigenesis remains to be investigated. The aim of this study is to in...
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| Veröffentlicht in: | Gut 2023-06, Vol.72 (Suppl 1), p.A3-A3 |
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| description | BackgroundIt has been reported that protein kinase cAMP-dependent type II regulatory subunit alpha (PRKAR2A) directly modulates some signaling pathways and is essential for colitis regulation, but its role in colitis-associated tumorigenesis remains to be investigated. The aim of this study is to investigate the function and underlying mechanisms of PRKAR2A in the formation of colitis-associated cancer (CAC).MethodsWe generated global Prkar2a knockout (Prkar2a -/-) mice and placed them on an azoxymethane (AOM)/dextran sodium sulfate (DSS) experimental CAC protocol. The biological function of PRKAR2A was investigated in vivo. PRKAR2A interacting protein was identified by co-immunoprecipitation (co-IP) and mass spectrometry. The downstream pathways regulated by PRKAR2A were identified by RNA-seq and Western Blot assays. γ-H2A.X foci detected by immunofluorescence were used to determine the extent of DNA damage and repair.ResultsKnockout of Prkar2a in mice significantly inhibited CAC formation. In response to AOM/DSS, Prkar2a -/- mice showed a decrease in intestinal injury and inflammatory tumorigenesis as assessed by colon length (P |
| doi_str_mv | 10.1136/gutjnl-2023-IDDF.2 |
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| fullrecord | <record><control><sourceid>proquest_bmj_j</sourceid><recordid>TN_cdi_proquest_journals_2825024005</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2825024005</sourcerecordid><originalsourceid>FETCH-LOGICAL-b675-f6530bbafea273152bfdef493d919f02f5a555881f80444052fe2bddc99343ca3</originalsourceid><addsrcrecordid>eNpFkL1OwzAUhS0EEqXwAkyWmF2u_xJnDP2BiiJQ2wUxWE5il0RtArEjVhZelCehoUhMd_nuOUcfQpcURpTy6HrThareEgaMk_lkMhuxIzSgIlKEM6WO0QCAxkTGIjlFZ95XAKBUQgfopad_39KbFQEq4fvz62l5ny5Ziss62NbkweOPMrzi6cPqGYcGv7XNrgkW5822DKUnxvsmL02wBQ7drmnLja2tL_05OnFm6-3F3x2i9Wy6Ht-RxePtfJwuSBbFkrhIcsgy46xhMaeSZa6wTiS8SGjigDlppJRKUadACAGSOcuyosiThAueGz5EV4fY_a73zvqgq6Zr632jZopJYAJA7qnRgcp21T9AQff-9MGf7kXo3ohm_AeD4GPy</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2825024005</pqid></control><display><type>article</type><title>IDDF2023-ABS-0150 PRKAR2A interacts with EMSY to promote colitis-associated tumorigenesis</title><source>PubMed Central</source><creator>Huang, Xinyang ; Jin, Yixun ; Wei, Lumin ; Wang, Zhuoxin ; Wang, Qi ; Wang, Lifu</creator><creatorcontrib>Huang, Xinyang ; Jin, Yixun ; Wei, Lumin ; Wang, Zhuoxin ; Wang, Qi ; Wang, Lifu</creatorcontrib><description>BackgroundIt has been reported that protein kinase cAMP-dependent type II regulatory subunit alpha (PRKAR2A) directly modulates some signaling pathways and is essential for colitis regulation, but its role in colitis-associated tumorigenesis remains to be investigated. The aim of this study is to investigate the function and underlying mechanisms of PRKAR2A in the formation of colitis-associated cancer (CAC).MethodsWe generated global Prkar2a knockout (Prkar2a -/-) mice and placed them on an azoxymethane (AOM)/dextran sodium sulfate (DSS) experimental CAC protocol. The biological function of PRKAR2A was investigated in vivo. PRKAR2A interacting protein was identified by co-immunoprecipitation (co-IP) and mass spectrometry. The downstream pathways regulated by PRKAR2A were identified by RNA-seq and Western Blot assays. γ-H2A.X foci detected by immunofluorescence were used to determine the extent of DNA damage and repair.ResultsKnockout of Prkar2a in mice significantly inhibited CAC formation. In response to AOM/DSS, Prkar2a -/- mice showed a decrease in intestinal injury and inflammatory tumorigenesis as assessed by colon length (P<0.001), tumor incidence, and tumor numbers (P<0.05) compared with wild-type cohorts. Ectopic expression of PRKAR2A significantly decreased the expression of epithelial cadherin in colon epithelium cell lines NCM460 and HCoEpiC. Conversely, the silencing of PRKAR2A in these two cell lines produced the opposite effect. Mechanistically, enrichment analysis of RNA-seq data suggested PRKAR2A exerted tumorigenesis effects through affecting DNA repair signaling pathway. In keeping with this, PRKAR2A-overexpressed colon epithelium cells induced by lipopolysaccharide displayed increased numbers of γ-H2A.X foci compared with the control group. EMSY, a pro-oncogenic chromatin remodeler implied in DNA damage repair, was identified as a direct effector of PRKAR2A by co-IP assay followed by mass spectrometry. We further demonstrated that EMSY was upregulated in PRKAR2A-overexpressed NCM460, accordingly, depletion of PRKAR2A decreased the expression of EMSY.ConclusionsPRKAR2A promotes the formation of CAC by inhibiting DNA damage repair via cooperating with EMSY. PRKAR2A may serve as a potential target for protecting patients with colitis from tumorigenesis.</description><identifier>ISSN: 0017-5749</identifier><identifier>EISSN: 1468-3288</identifier><identifier>DOI: 10.1136/gutjnl-2023-IDDF.2</identifier><language>eng</language><publisher>London: BMJ Publishing Group Ltd and British Society of Gastroenterology</publisher><subject>Azoxymethane ; Cadherins ; Chromatin ; Colitis ; Colon ; Colorectal cancer ; Deoxyribonucleic acid ; Dextran ; DNA ; DNA damage ; DNA repair ; E-cadherin ; Ectopic expression ; Epithelium ; Gut – IDDF Young Investigator Award ; Immunofluorescence ; Immunoprecipitation ; Inflammation ; Inflammatory bowel disease ; Kinases ; Lipopolysaccharides ; Mass spectrometry ; Mass spectroscopy ; Protein kinase C ; Scientific imaging ; Signal transduction ; Sodium sulfate ; Tumorigenesis</subject><ispartof>Gut, 2023-06, Vol.72 (Suppl 1), p.A3-A3</ispartof><rights>Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.</rights><rights>2023 Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids></links><search><creatorcontrib>Huang, Xinyang</creatorcontrib><creatorcontrib>Jin, Yixun</creatorcontrib><creatorcontrib>Wei, Lumin</creatorcontrib><creatorcontrib>Wang, Zhuoxin</creatorcontrib><creatorcontrib>Wang, Qi</creatorcontrib><creatorcontrib>Wang, Lifu</creatorcontrib><title>IDDF2023-ABS-0150 PRKAR2A interacts with EMSY to promote colitis-associated tumorigenesis</title><title>Gut</title><addtitle>Gut</addtitle><description>BackgroundIt has been reported that protein kinase cAMP-dependent type II regulatory subunit alpha (PRKAR2A) directly modulates some signaling pathways and is essential for colitis regulation, but its role in colitis-associated tumorigenesis remains to be investigated. The aim of this study is to investigate the function and underlying mechanisms of PRKAR2A in the formation of colitis-associated cancer (CAC).MethodsWe generated global Prkar2a knockout (Prkar2a -/-) mice and placed them on an azoxymethane (AOM)/dextran sodium sulfate (DSS) experimental CAC protocol. The biological function of PRKAR2A was investigated in vivo. PRKAR2A interacting protein was identified by co-immunoprecipitation (co-IP) and mass spectrometry. The downstream pathways regulated by PRKAR2A were identified by RNA-seq and Western Blot assays. γ-H2A.X foci detected by immunofluorescence were used to determine the extent of DNA damage and repair.ResultsKnockout of Prkar2a in mice significantly inhibited CAC formation. In response to AOM/DSS, Prkar2a -/- mice showed a decrease in intestinal injury and inflammatory tumorigenesis as assessed by colon length (P<0.001), tumor incidence, and tumor numbers (P<0.05) compared with wild-type cohorts. Ectopic expression of PRKAR2A significantly decreased the expression of epithelial cadherin in colon epithelium cell lines NCM460 and HCoEpiC. Conversely, the silencing of PRKAR2A in these two cell lines produced the opposite effect. Mechanistically, enrichment analysis of RNA-seq data suggested PRKAR2A exerted tumorigenesis effects through affecting DNA repair signaling pathway. In keeping with this, PRKAR2A-overexpressed colon epithelium cells induced by lipopolysaccharide displayed increased numbers of γ-H2A.X foci compared with the control group. EMSY, a pro-oncogenic chromatin remodeler implied in DNA damage repair, was identified as a direct effector of PRKAR2A by co-IP assay followed by mass spectrometry. We further demonstrated that EMSY was upregulated in PRKAR2A-overexpressed NCM460, accordingly, depletion of PRKAR2A decreased the expression of EMSY.ConclusionsPRKAR2A promotes the formation of CAC by inhibiting DNA damage repair via cooperating with EMSY. PRKAR2A may serve as a potential target for protecting patients with colitis from tumorigenesis.</description><subject>Azoxymethane</subject><subject>Cadherins</subject><subject>Chromatin</subject><subject>Colitis</subject><subject>Colon</subject><subject>Colorectal cancer</subject><subject>Deoxyribonucleic acid</subject><subject>Dextran</subject><subject>DNA</subject><subject>DNA damage</subject><subject>DNA repair</subject><subject>E-cadherin</subject><subject>Ectopic expression</subject><subject>Epithelium</subject><subject>Gut – IDDF Young Investigator Award</subject><subject>Immunofluorescence</subject><subject>Immunoprecipitation</subject><subject>Inflammation</subject><subject>Inflammatory bowel disease</subject><subject>Kinases</subject><subject>Lipopolysaccharides</subject><subject>Mass spectrometry</subject><subject>Mass spectroscopy</subject><subject>Protein kinase C</subject><subject>Scientific imaging</subject><subject>Signal transduction</subject><subject>Sodium sulfate</subject><subject>Tumorigenesis</subject><issn>0017-5749</issn><issn>1468-3288</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><recordid>eNpFkL1OwzAUhS0EEqXwAkyWmF2u_xJnDP2BiiJQ2wUxWE5il0RtArEjVhZelCehoUhMd_nuOUcfQpcURpTy6HrThareEgaMk_lkMhuxIzSgIlKEM6WO0QCAxkTGIjlFZ95XAKBUQgfopad_39KbFQEq4fvz62l5ny5Ziss62NbkweOPMrzi6cPqGYcGv7XNrgkW5822DKUnxvsmL02wBQ7drmnLja2tL_05OnFm6-3F3x2i9Wy6Ht-RxePtfJwuSBbFkrhIcsgy46xhMaeSZa6wTiS8SGjigDlppJRKUadACAGSOcuyosiThAueGz5EV4fY_a73zvqgq6Zr632jZopJYAJA7qnRgcp21T9AQff-9MGf7kXo3ohm_AeD4GPy</recordid><startdate>20230609</startdate><enddate>20230609</enddate><creator>Huang, Xinyang</creator><creator>Jin, Yixun</creator><creator>Wei, Lumin</creator><creator>Wang, Zhuoxin</creator><creator>Wang, Qi</creator><creator>Wang, Lifu</creator><general>BMJ Publishing Group Ltd and British Society of Gastroenterology</general><general>BMJ Publishing Group LTD</general><scope>K9.</scope></search><sort><creationdate>20230609</creationdate><title>IDDF2023-ABS-0150 PRKAR2A interacts with EMSY to promote colitis-associated tumorigenesis</title><author>Huang, Xinyang ; Jin, Yixun ; Wei, Lumin ; Wang, Zhuoxin ; Wang, Qi ; Wang, Lifu</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-b675-f6530bbafea273152bfdef493d919f02f5a555881f80444052fe2bddc99343ca3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Azoxymethane</topic><topic>Cadherins</topic><topic>Chromatin</topic><topic>Colitis</topic><topic>Colon</topic><topic>Colorectal cancer</topic><topic>Deoxyribonucleic acid</topic><topic>Dextran</topic><topic>DNA</topic><topic>DNA damage</topic><topic>DNA repair</topic><topic>E-cadherin</topic><topic>Ectopic expression</topic><topic>Epithelium</topic><topic>Gut – IDDF Young Investigator Award</topic><topic>Immunofluorescence</topic><topic>Immunoprecipitation</topic><topic>Inflammation</topic><topic>Inflammatory bowel disease</topic><topic>Kinases</topic><topic>Lipopolysaccharides</topic><topic>Mass spectrometry</topic><topic>Mass spectroscopy</topic><topic>Protein kinase C</topic><topic>Scientific imaging</topic><topic>Signal transduction</topic><topic>Sodium sulfate</topic><topic>Tumorigenesis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Huang, Xinyang</creatorcontrib><creatorcontrib>Jin, Yixun</creatorcontrib><creatorcontrib>Wei, Lumin</creatorcontrib><creatorcontrib>Wang, Zhuoxin</creatorcontrib><creatorcontrib>Wang, Qi</creatorcontrib><creatorcontrib>Wang, Lifu</creatorcontrib><collection>ProQuest Health & Medical Complete (Alumni)</collection><jtitle>Gut</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Huang, Xinyang</au><au>Jin, Yixun</au><au>Wei, Lumin</au><au>Wang, Zhuoxin</au><au>Wang, Qi</au><au>Wang, Lifu</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>IDDF2023-ABS-0150 PRKAR2A interacts with EMSY to promote colitis-associated tumorigenesis</atitle><jtitle>Gut</jtitle><stitle>Gut</stitle><date>2023-06-09</date><risdate>2023</risdate><volume>72</volume><issue>Suppl 1</issue><spage>A3</spage><epage>A3</epage><pages>A3-A3</pages><issn>0017-5749</issn><eissn>1468-3288</eissn><abstract>BackgroundIt has been reported that protein kinase cAMP-dependent type II regulatory subunit alpha (PRKAR2A) directly modulates some signaling pathways and is essential for colitis regulation, but its role in colitis-associated tumorigenesis remains to be investigated. The aim of this study is to investigate the function and underlying mechanisms of PRKAR2A in the formation of colitis-associated cancer (CAC).MethodsWe generated global Prkar2a knockout (Prkar2a -/-) mice and placed them on an azoxymethane (AOM)/dextran sodium sulfate (DSS) experimental CAC protocol. The biological function of PRKAR2A was investigated in vivo. PRKAR2A interacting protein was identified by co-immunoprecipitation (co-IP) and mass spectrometry. The downstream pathways regulated by PRKAR2A were identified by RNA-seq and Western Blot assays. γ-H2A.X foci detected by immunofluorescence were used to determine the extent of DNA damage and repair.ResultsKnockout of Prkar2a in mice significantly inhibited CAC formation. In response to AOM/DSS, Prkar2a -/- mice showed a decrease in intestinal injury and inflammatory tumorigenesis as assessed by colon length (P<0.001), tumor incidence, and tumor numbers (P<0.05) compared with wild-type cohorts. Ectopic expression of PRKAR2A significantly decreased the expression of epithelial cadherin in colon epithelium cell lines NCM460 and HCoEpiC. Conversely, the silencing of PRKAR2A in these two cell lines produced the opposite effect. Mechanistically, enrichment analysis of RNA-seq data suggested PRKAR2A exerted tumorigenesis effects through affecting DNA repair signaling pathway. In keeping with this, PRKAR2A-overexpressed colon epithelium cells induced by lipopolysaccharide displayed increased numbers of γ-H2A.X foci compared with the control group. EMSY, a pro-oncogenic chromatin remodeler implied in DNA damage repair, was identified as a direct effector of PRKAR2A by co-IP assay followed by mass spectrometry. We further demonstrated that EMSY was upregulated in PRKAR2A-overexpressed NCM460, accordingly, depletion of PRKAR2A decreased the expression of EMSY.ConclusionsPRKAR2A promotes the formation of CAC by inhibiting DNA damage repair via cooperating with EMSY. PRKAR2A may serve as a potential target for protecting patients with colitis from tumorigenesis.</abstract><cop>London</cop><pub>BMJ Publishing Group Ltd and British Society of Gastroenterology</pub><doi>10.1136/gutjnl-2023-IDDF.2</doi></addata></record> |
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| subjects | Azoxymethane Cadherins Chromatin Colitis Colon Colorectal cancer Deoxyribonucleic acid Dextran DNA DNA damage DNA repair E-cadherin Ectopic expression Epithelium Gut – IDDF Young Investigator Award Immunofluorescence Immunoprecipitation Inflammation Inflammatory bowel disease Kinases Lipopolysaccharides Mass spectrometry Mass spectroscopy Protein kinase C Scientific imaging Signal transduction Sodium sulfate Tumorigenesis |
| title | IDDF2023-ABS-0150 PRKAR2A interacts with EMSY to promote colitis-associated tumorigenesis |
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