Lei Li, Ning Yang, Jian-Hong Sun, Li-Juan Wei, Yuan Gao
{"title":"USP49的N6-甲基腺苷修饰依赖于IGF2BP3,它通过调节SIRT1的稳定性增强自噬作用,从而促进视网膜母细胞瘤的卡铂抗性。","authors":"Lei Li, Ning Yang, Jian-Hong Sun, Li-Juan Wei, Yuan Gao","doi":"10.1002/kjm2.12902","DOIUrl":null,"url":null,"abstract":"<p><p>Retinoblastoma (RB) poses significant challenges in clinical management due to the emergence of resistance to conventional chemotherapeutic agents, particularly carboplatin (CBP). In this study, we investigated the molecular mechanisms underlying CBP resistance in RB, with a focus on the role of autophagy and the influence of ubiquitin-specific peptidase 49 (USP49). We observed upregulation of USP49 in RB tissues and cell lines, correlating with disease progression. Functional assays revealed that USP49 promoted aggressive proliferation and conferred CBP resistance in RB cells. Furthermore, USP49 accelerated tumor growth and induced CBP resistance in vivo. Mechanistically, we found that USP49 facilitated CBP resistance by promoting autophagy activation. In addition, we identified insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3)-mediated N6-methyladenosine (m<sup>6</sup>A) modification of USP49 as a regulatory mechanism, wherein IGF2BP3 upregulated USP49 expression in an m<sup>6</sup>A-dependent manner. Moreover, USP49 stabilized SIRT1, a protein associated with CBP resistance and autophagy, by inhibiting its ubiquitination and degradation. Rescue experiments confirmed the pivotal role of SIRT1 in USP49-mediated CBP resistance. Our findings delineate a novel molecular network involving USP49-mediated autophagy in promoting CBP resistance in RB, offering potential targets for therapeutic intervention to enhance treatment efficacy and improve outcomes for RB patients.</p>","PeriodicalId":94244,"journal":{"name":"The Kaohsiung journal of medical sciences","volume":" ","pages":"1043-1056"},"PeriodicalIF":0.0000,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11618494/pdf/","citationCount":"0","resultStr":"{\"title\":\"IGF2BP3-dependent N6-methyladenosine modification of USP49 promotes carboplatin resistance in retinoblastoma by enhancing autophagy via regulating the stabilization of SIRT1.\",\"authors\":\"Lei Li, Ning Yang, Jian-Hong Sun, Li-Juan Wei, Yuan Gao\",\"doi\":\"10.1002/kjm2.12902\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Retinoblastoma (RB) poses significant challenges in clinical management due to the emergence of resistance to conventional chemotherapeutic agents, particularly carboplatin (CBP). In this study, we investigated the molecular mechanisms underlying CBP resistance in RB, with a focus on the role of autophagy and the influence of ubiquitin-specific peptidase 49 (USP49). We observed upregulation of USP49 in RB tissues and cell lines, correlating with disease progression. Functional assays revealed that USP49 promoted aggressive proliferation and conferred CBP resistance in RB cells. Furthermore, USP49 accelerated tumor growth and induced CBP resistance in vivo. Mechanistically, we found that USP49 facilitated CBP resistance by promoting autophagy activation. In addition, we identified insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3)-mediated N6-methyladenosine (m<sup>6</sup>A) modification of USP49 as a regulatory mechanism, wherein IGF2BP3 upregulated USP49 expression in an m<sup>6</sup>A-dependent manner. Moreover, USP49 stabilized SIRT1, a protein associated with CBP resistance and autophagy, by inhibiting its ubiquitination and degradation. Rescue experiments confirmed the pivotal role of SIRT1 in USP49-mediated CBP resistance. Our findings delineate a novel molecular network involving USP49-mediated autophagy in promoting CBP resistance in RB, offering potential targets for therapeutic intervention to enhance treatment efficacy and improve outcomes for RB patients.</p>\",\"PeriodicalId\":94244,\"journal\":{\"name\":\"The Kaohsiung journal of medical sciences\",\"volume\":\" \",\"pages\":\"1043-1056\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2024-12-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11618494/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"The Kaohsiung journal of medical sciences\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1002/kjm2.12902\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/11/4 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"The Kaohsiung journal of medical sciences","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1002/kjm2.12902","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/11/4 0:00:00","PubModel":"Epub","JCR":"","JCRName":"","Score":null,"Total":0}
IGF2BP3-dependent N6-methyladenosine modification of USP49 promotes carboplatin resistance in retinoblastoma by enhancing autophagy via regulating the stabilization of SIRT1.
Retinoblastoma (RB) poses significant challenges in clinical management due to the emergence of resistance to conventional chemotherapeutic agents, particularly carboplatin (CBP). In this study, we investigated the molecular mechanisms underlying CBP resistance in RB, with a focus on the role of autophagy and the influence of ubiquitin-specific peptidase 49 (USP49). We observed upregulation of USP49 in RB tissues and cell lines, correlating with disease progression. Functional assays revealed that USP49 promoted aggressive proliferation and conferred CBP resistance in RB cells. Furthermore, USP49 accelerated tumor growth and induced CBP resistance in vivo. Mechanistically, we found that USP49 facilitated CBP resistance by promoting autophagy activation. In addition, we identified insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3)-mediated N6-methyladenosine (m6A) modification of USP49 as a regulatory mechanism, wherein IGF2BP3 upregulated USP49 expression in an m6A-dependent manner. Moreover, USP49 stabilized SIRT1, a protein associated with CBP resistance and autophagy, by inhibiting its ubiquitination and degradation. Rescue experiments confirmed the pivotal role of SIRT1 in USP49-mediated CBP resistance. Our findings delineate a novel molecular network involving USP49-mediated autophagy in promoting CBP resistance in RB, offering potential targets for therapeutic intervention to enhance treatment efficacy and improve outcomes for RB patients.