Tejinder Pal Khaket, Suman Rimal, Xingjun Wang, Sunil Bhurtel, Yen-Chi Wu, Bingwei Lu
{"title":"c-myc 翻译过程中的核糖体停滞是可操作的癌细胞脆弱性。","authors":"Tejinder Pal Khaket, Suman Rimal, Xingjun Wang, Sunil Bhurtel, Yen-Chi Wu, Bingwei Lu","doi":"10.1093/pnasnexus/pgae321","DOIUrl":null,"url":null,"abstract":"<p><p>Myc is a major driver of tumor initiation, progression, and maintenance. Up-regulation of Myc protein level rather than acquisition of neomorphic properties appears to underlie most Myc-driven cancers. Cellular mechanisms governing Myc expression remain incompletely defined. In this study, we show that ribosome-associated quality control (RQC) plays a critical role in maintaining Myc protein level. Ribosomes stall during the synthesis of the N-terminal portion of cMyc, generating aberrant cMyc species and necessitating deployment of the early RQC factor ZNF598 to handle translational stress and restore <i>cMyc</i> translation. ZNF598 expression is up-regulated in human glioblastoma (GBM), and its expression positively correlates with that of cMyc. ZNF598 knockdown inhibits human GBM neurosphere formation in cell culture and Myc-dependent tumor growth in vivo in <i>Drosophila</i>. Intriguingly, the SARS-COV-2-encoded translational regulator Nsp1 impinges on ZNF598 to restrain cMyc translation and consequently cMyc-dependent cancer growth. Remarkably, Nsp1 exhibits synthetic toxicity with the translation and RQC-related factor ATP-binding cassette subfamily E member 1, which, despite its normally positive correlation with cMyc in cancer cells, is co-opted by Nsp1 to down-regulate cMyc and inhibit tumor growth. Ribosome stalling during <i>c-myc</i> translation thus offers actionable cancer cell vulnerability.</p>","PeriodicalId":74468,"journal":{"name":"PNAS nexus","volume":null,"pages":null},"PeriodicalIF":2.2000,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11330866/pdf/","citationCount":"0","resultStr":"{\"title\":\"Ribosome stalling during <i>c-myc</i> translation presents actionable cancer cell vulnerability.\",\"authors\":\"Tejinder Pal Khaket, Suman Rimal, Xingjun Wang, Sunil Bhurtel, Yen-Chi Wu, Bingwei Lu\",\"doi\":\"10.1093/pnasnexus/pgae321\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Myc is a major driver of tumor initiation, progression, and maintenance. Up-regulation of Myc protein level rather than acquisition of neomorphic properties appears to underlie most Myc-driven cancers. Cellular mechanisms governing Myc expression remain incompletely defined. In this study, we show that ribosome-associated quality control (RQC) plays a critical role in maintaining Myc protein level. Ribosomes stall during the synthesis of the N-terminal portion of cMyc, generating aberrant cMyc species and necessitating deployment of the early RQC factor ZNF598 to handle translational stress and restore <i>cMyc</i> translation. ZNF598 expression is up-regulated in human glioblastoma (GBM), and its expression positively correlates with that of cMyc. ZNF598 knockdown inhibits human GBM neurosphere formation in cell culture and Myc-dependent tumor growth in vivo in <i>Drosophila</i>. Intriguingly, the SARS-COV-2-encoded translational regulator Nsp1 impinges on ZNF598 to restrain cMyc translation and consequently cMyc-dependent cancer growth. Remarkably, Nsp1 exhibits synthetic toxicity with the translation and RQC-related factor ATP-binding cassette subfamily E member 1, which, despite its normally positive correlation with cMyc in cancer cells, is co-opted by Nsp1 to down-regulate cMyc and inhibit tumor growth. Ribosome stalling during <i>c-myc</i> translation thus offers actionable cancer cell vulnerability.</p>\",\"PeriodicalId\":74468,\"journal\":{\"name\":\"PNAS nexus\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":2.2000,\"publicationDate\":\"2024-08-13\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11330866/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"PNAS nexus\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1093/pnasnexus/pgae321\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/8/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q2\",\"JCRName\":\"MULTIDISCIPLINARY SCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"PNAS nexus","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1093/pnasnexus/pgae321","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/8/1 0:00:00","PubModel":"eCollection","JCR":"Q2","JCRName":"MULTIDISCIPLINARY SCIENCES","Score":null,"Total":0}
Ribosome stalling during c-myc translation presents actionable cancer cell vulnerability.
Myc is a major driver of tumor initiation, progression, and maintenance. Up-regulation of Myc protein level rather than acquisition of neomorphic properties appears to underlie most Myc-driven cancers. Cellular mechanisms governing Myc expression remain incompletely defined. In this study, we show that ribosome-associated quality control (RQC) plays a critical role in maintaining Myc protein level. Ribosomes stall during the synthesis of the N-terminal portion of cMyc, generating aberrant cMyc species and necessitating deployment of the early RQC factor ZNF598 to handle translational stress and restore cMyc translation. ZNF598 expression is up-regulated in human glioblastoma (GBM), and its expression positively correlates with that of cMyc. ZNF598 knockdown inhibits human GBM neurosphere formation in cell culture and Myc-dependent tumor growth in vivo in Drosophila. Intriguingly, the SARS-COV-2-encoded translational regulator Nsp1 impinges on ZNF598 to restrain cMyc translation and consequently cMyc-dependent cancer growth. Remarkably, Nsp1 exhibits synthetic toxicity with the translation and RQC-related factor ATP-binding cassette subfamily E member 1, which, despite its normally positive correlation with cMyc in cancer cells, is co-opted by Nsp1 to down-regulate cMyc and inhibit tumor growth. Ribosome stalling during c-myc translation thus offers actionable cancer cell vulnerability.