FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W4323351763> ?p ?o ?g. }

• W4323351763 endingPage "1292" @default.
• W4323351763 startingPage "1279" @default.
• W4323351763 abstract "Background & AimsDespite recent progress, long-term survival remains low for hepatocellular carcinoma (HCC). The most effective HCC therapies target the tumor immune microenvironment (TIME), and there are almost no therapies that directly target tumor cells. Here, we investigated the regulation and function of tumor cell-expressed Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) in HCC.MethodsHCC was induced in mice by Sleeping Beauty-mediated expression of MET, CTNNB1-S45Y, or TAZ-S89A, or by diethylnitrosamine plus CCl4. Hepatocellular TAZ and YAP were deleted in floxed mice via adeno-associated virus serotype 8-mediated expression of Cre. TAZ target genes were identified from RNA sequencing, confirmed by chromatin immunoprecipitation, and evaluated in a clustered regularly interspaced short palindromic repeats interference (CRISPRi) screen. TEA domain transcription factors (TEADs), anillin (ANLN), Kif23, and programmed cell death protein ligand 1 were knocked down by guide RNAs in dead clustered regularly interspaced short palindromic repeats–associated protein 9 (dCas9) knock-in mice.ResultsYAP and TAZ were up-regulated in murine and human HCC, but only deletion of TAZ consistently decreased HCC growth and mortality. Conversely, overexpression of activated TAZ was sufficient to trigger HCC. TAZ expression in HCC was regulated by cholesterol synthesis, as demonstrated by pharmacologic or genetic inhibition of 3-hydroxy-3-methylglutaryl- coenzyme A reductase (HMGCR), farnesyl pyrophosphate synthase, farnesyl-diphosphate farnesyltransferase 1 (FDFT1), or sterol regulatory element-binding protein 2 (SREBP2). TAZ- and MET/CTNNB1-S45Y–driven HCC required the expression of TEAD2 and, to a lesser extent, TEAD4. Accordingly, TEAD2 displayed the most profound effect on survival in patients with HCC. TAZ and TEAD2 promoted HCC via increased tumor cell proliferation, mediated by TAZ target genes ANLN and kinesin family member 23 (KIF23). Therapeutic targeting of HCC, using pan-TEAD inhibitors or the combination of a statin with sorafenib or anti–programmed cell death protein 1, decreased tumor growth.ConclusionsOur results suggest the cholesterol-TAZ-TEAD2-ANLN/KIF23 pathway as a mediator of HCC proliferation and tumor cell-intrinsic therapeutic target that could be synergistically combined with TIME-targeted therapies. Despite recent progress, long-term survival remains low for hepatocellular carcinoma (HCC). The most effective HCC therapies target the tumor immune microenvironment (TIME), and there are almost no therapies that directly target tumor cells. Here, we investigated the regulation and function of tumor cell-expressed Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) in HCC. HCC was induced in mice by Sleeping Beauty-mediated expression of MET, CTNNB1-S45Y, or TAZ-S89A, or by diethylnitrosamine plus CCl4. Hepatocellular TAZ and YAP were deleted in floxed mice via adeno-associated virus serotype 8-mediated expression of Cre. TAZ target genes were identified from RNA sequencing, confirmed by chromatin immunoprecipitation, and evaluated in a clustered regularly interspaced short palindromic repeats interference (CRISPRi) screen. TEA domain transcription factors (TEADs), anillin (ANLN), Kif23, and programmed cell death protein ligand 1 were knocked down by guide RNAs in dead clustered regularly interspaced short palindromic repeats–associated protein 9 (dCas9) knock-in mice. YAP and TAZ were up-regulated in murine and human HCC, but only deletion of TAZ consistently decreased HCC growth and mortality. Conversely, overexpression of activated TAZ was sufficient to trigger HCC. TAZ expression in HCC was regulated by cholesterol synthesis, as demonstrated by pharmacologic or genetic inhibition of 3-hydroxy-3-methylglutaryl- coenzyme A reductase (HMGCR), farnesyl pyrophosphate synthase, farnesyl-diphosphate farnesyltransferase 1 (FDFT1), or sterol regulatory element-binding protein 2 (SREBP2). TAZ- and MET/CTNNB1-S45Y–driven HCC required the expression of TEAD2 and, to a lesser extent, TEAD4. Accordingly, TEAD2 displayed the most profound effect on survival in patients with HCC. TAZ and TEAD2 promoted HCC via increased tumor cell proliferation, mediated by TAZ target genes ANLN and kinesin family member 23 (KIF23). Therapeutic targeting of HCC, using pan-TEAD inhibitors or the combination of a statin with sorafenib or anti–programmed cell death protein 1, decreased tumor growth. Our results suggest the cholesterol-TAZ-TEAD2-ANLN/KIF23 pathway as a mediator of HCC proliferation and tumor cell-intrinsic therapeutic target that could be synergistically combined with TIME-targeted therapies." @default.
• W4323351763 created "2023-03-08" @default.
• W4323351763 creator A5001563233 @default.
• W4323351763 creator A5007607351 @default.
• W4323351763 creator A5010970397 @default.
• W4323351763 creator A5027075602 @default.
• W4323351763 creator A5027322897 @default.
• W4323351763 creator A5041709694 @default.
• W4323351763 creator A5053831076 @default.
• W4323351763 creator A5057292712 @default.
• W4323351763 creator A5058002880 @default.
• W4323351763 creator A5073738784 @default.
• W4323351763 creator A5078662102 @default.
• W4323351763 creator A5079198469 @default.
• W4323351763 date "2023-06-01" @default.
• W4323351763 modified "2023-10-17" @default.
• W4323351763 title "A Therapeutically Targetable TAZ-TEAD2 Pathway Drives the Growth of Hepatocellular Carcinoma via ANLN and KIF23" @default.
• W4323351763 cites W1971837077 @default.
• W4323351763 cites W1982498121 @default.
• W4323351763 cites W1995160678 @default.
• W4323351763 cites W2004480757 @default.
• W4323351763 cites W2006548076 @default.
• W4323351763 cites W2034469841 @default.
• W4323351763 cites W2060914434 @default.
• W4323351763 cites W2073157874 @default.
• W4323351763 cites W2078811578 @default.
• W4323351763 cites W2099062342 @default.
• W4323351763 cites W2100641053 @default.
• W4323351763 cites W2126712555 @default.
• W4323351763 cites W2134987468 @default.
• W4323351763 cites W2146544786 @default.
• W4323351763 cites W2151260549 @default.
• W4323351763 cites W2159038842 @default.
• W4323351763 cites W2165684233 @default.
• W4323351763 cites W2201931409 @default.
• W4323351763 cites W2290526242 @default.
• W4323351763 cites W2294765885 @default.
• W4323351763 cites W2530537049 @default.
• W4323351763 cites W2541359632 @default.
• W4323351763 cites W2586159641 @default.
• W4323351763 cites W2601868035 @default.
• W4323351763 cites W2606367731 @default.
• W4323351763 cites W2612611322 @default.
• W4323351763 cites W2766367284 @default.
• W4323351763 cites W2780234747 @default.
• W4323351763 cites W2783581317 @default.
• W4323351763 cites W2810909862 @default.
• W4323351763 cites W2884435515 @default.
• W4323351763 cites W2885305111 @default.
• W4323351763 cites W2899174828 @default.
• W4323351763 cites W2904492726 @default.
• W4323351763 cites W2905891236 @default.
• W4323351763 cites W2909312563 @default.
• W4323351763 cites W2912128540 @default.
• W4323351763 cites W2915108688 @default.
• W4323351763 cites W2923661246 @default.
• W4323351763 cites W2923753502 @default.
• W4323351763 cites W2952311394 @default.
• W4323351763 cites W2964645794 @default.
• W4323351763 cites W2969516088 @default.
• W4323351763 cites W2972904585 @default.
• W4323351763 cites W2990562645 @default.
• W4323351763 cites W2990602950 @default.
• W4323351763 cites W3000126395 @default.
• W4323351763 cites W3015115032 @default.
• W4323351763 cites W3025022288 @default.
• W4323351763 cites W3036513507 @default.
• W4323351763 cites W3154759454 @default.
• W4323351763 cites W3198862328 @default.
• W4323351763 cites W4200005504 @default.
• W4323351763 cites W4200158019 @default.
• W4323351763 cites W4210774372 @default.
• W4323351763 cites W4226455181 @default.
• W4323351763 cites W4232620598 @default.
• W4323351763 cites W4252021281 @default.
• W4323351763 cites W4302010968 @default.
• W4323351763 cites W7323818 @default.
• W4323351763 doi "https://doi.org/10.1053/j.gastro.2023.02.043" @default.
• W4323351763 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/36894036" @default.
• W4323351763 hasPublicationYear "2023" @default.
• W4323351763 type Work @default.
• W4323351763 citedByCount "1" @default.
• W4323351763 countsByYear W43233517632023 @default.
• W4323351763 crossrefType "journal-article" @default.
• W4323351763 hasAuthorship W4323351763A5001563233 @default.
• W4323351763 hasAuthorship W4323351763A5007607351 @default.
• W4323351763 hasAuthorship W4323351763A5010970397 @default.
• W4323351763 hasAuthorship W4323351763A5027075602 @default.
• W4323351763 hasAuthorship W4323351763A5027322897 @default.
• W4323351763 hasAuthorship W4323351763A5041709694 @default.
• W4323351763 hasAuthorship W4323351763A5053831076 @default.
• W4323351763 hasAuthorship W4323351763A5057292712 @default.
• W4323351763 hasAuthorship W4323351763A5058002880 @default.
• W4323351763 hasAuthorship W4323351763A5073738784 @default.
• W4323351763 hasAuthorship W4323351763A5078662102 @default.
• W4323351763 hasAuthorship W4323351763A5079198469 @default.
• W4323351763 hasBestOaLocation W43233517631 @default.
• W4323351763 hasConcept C101762097 @default.

• next