{"title":"RBM5以三明治模式招募MGC32805,诱导ΔFAS新抗原并触发FAS特性转换:在结直肠癌中的意义","authors":"Huizhe Wu, Xiaoyun Hu, Yilin Wang, Xianglong Zhu, Qing Zhao, Yingqi Zhao, Wanlin Cui, Mingrong Zhang, Haishan Zhao, Kai Li, Minjie Wei","doi":"10.1038/s41388-025-03390-4","DOIUrl":null,"url":null,"abstract":"<p><p>Pre-mRNA alternative splicing (AS) is a crucial process, which plays a significant role in inducing tumor subtype-specific alterations and the hallmark of epigenetic heterogeneity in tumorigenesis. However, the regulatory mechanisms of pre-mRNA AS remain obscure. This study demonstrates that splicing factor RBM5 recruits long non-coding RNA MGC32805, and they act in concert as oncogenes in colorectal cancer (CRC) cells by preventing apoptosis, as well as promoting migration and resistance to 5-Fluorouracil (5-FU). Specifically, they promote the exclusion of exon 6 in the FAS pre-mRNA, leading to decreased expression of mFAS (an apoptotic isoform) and increased expression of ΔFAS (an anti-apoptotic isoform) in both CRC cells and a mouse xenograft model. RBM5, which contains Leu650 and Arg681 residues in the ZnF-C2H2 domain, recognizes the \"GUACG\" (-1299 to -1303) motif in MGC32805. Furthermore, MGC32805 blocks the binding site (Lys645) of the E3 ubiquitin ligase PRPF19, which targets RBM5 for degradation, thus increasing the stability of RBM5. The His665 and Leu668 residues of RBM5 specifically bind to the FAS exon 6 adjacent element (GAACAAA), which drives FAS-AS events and increases the expression ratio of the ΔFAS/mFAS isoforms. These findings introduce a novel research strategy to investigate the epigenetic heterogeneity and plasticity of tumorigenesis. They also shed light on the mechanism of MGC32805-mediated transformation of the FAS tumor neoantigen function from a tumor suppressor to an oncogene at the AS level through its interactions with RBM5.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":7.3000,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"RBM5 recruiting MGC32805 in a sandwich mode and inducing ΔFAS neoantigen and triggering FAS properties switch: implication in colorectal cancer.\",\"authors\":\"Huizhe Wu, Xiaoyun Hu, Yilin Wang, Xianglong Zhu, Qing Zhao, Yingqi Zhao, Wanlin Cui, Mingrong Zhang, Haishan Zhao, Kai Li, Minjie Wei\",\"doi\":\"10.1038/s41388-025-03390-4\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Pre-mRNA alternative splicing (AS) is a crucial process, which plays a significant role in inducing tumor subtype-specific alterations and the hallmark of epigenetic heterogeneity in tumorigenesis. However, the regulatory mechanisms of pre-mRNA AS remain obscure. This study demonstrates that splicing factor RBM5 recruits long non-coding RNA MGC32805, and they act in concert as oncogenes in colorectal cancer (CRC) cells by preventing apoptosis, as well as promoting migration and resistance to 5-Fluorouracil (5-FU). Specifically, they promote the exclusion of exon 6 in the FAS pre-mRNA, leading to decreased expression of mFAS (an apoptotic isoform) and increased expression of ΔFAS (an anti-apoptotic isoform) in both CRC cells and a mouse xenograft model. RBM5, which contains Leu650 and Arg681 residues in the ZnF-C2H2 domain, recognizes the \\\"GUACG\\\" (-1299 to -1303) motif in MGC32805. Furthermore, MGC32805 blocks the binding site (Lys645) of the E3 ubiquitin ligase PRPF19, which targets RBM5 for degradation, thus increasing the stability of RBM5. The His665 and Leu668 residues of RBM5 specifically bind to the FAS exon 6 adjacent element (GAACAAA), which drives FAS-AS events and increases the expression ratio of the ΔFAS/mFAS isoforms. These findings introduce a novel research strategy to investigate the epigenetic heterogeneity and plasticity of tumorigenesis. They also shed light on the mechanism of MGC32805-mediated transformation of the FAS tumor neoantigen function from a tumor suppressor to an oncogene at the AS level through its interactions with RBM5.</p>\",\"PeriodicalId\":19524,\"journal\":{\"name\":\"Oncogene\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":7.3000,\"publicationDate\":\"2025-06-26\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Oncogene\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1038/s41388-025-03390-4\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Oncogene","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s41388-025-03390-4","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
前mrna选择性剪接(Pre-mRNA alternative splicing, AS)是诱导肿瘤亚型特异性改变的重要过程,是肿瘤发生过程中表观遗传异质性的标志。然而,pre-mRNA AS的调控机制尚不清楚。本研究表明,剪接因子RBM5招募长链非编码RNA MGC32805,并通过阻止结直肠癌(CRC)细胞凋亡、促进迁移和对5-氟尿嘧啶(5-FU)的抗性,在结直肠癌(CRC)细胞中作为癌基因协同作用。具体来说,它们促进FAS前mrna中外显子6的排除,导致CRC细胞和小鼠异种移植模型中mFAS(一种凋亡亚型)的表达减少,ΔFAS(一种抗凋亡亚型)的表达增加。RBM5在ZnF-C2H2结构域中含有Leu650和Arg681残基,可识别MGC32805中的GUACG(-1299至-1303)基序。此外,MGC32805阻断了E3泛素连接酶PRPF19的结合位点(Lys645),该酶以RBM5为降解靶点,从而提高了RBM5的稳定性。RBM5的His665和Leu668残基特异性结合FAS外显子6相邻元件(GAACAAA),驱动FAS- as事件并增加ΔFAS/mFAS亚型的表达率。这些发现为研究肿瘤发生的表观遗传异质性和可塑性提供了一种新的研究策略。他们还揭示了mgc32805介导的FAS肿瘤新抗原功能通过与RBM5的相互作用在AS水平上从肿瘤抑制因子转化为癌基因的机制。
RBM5 recruiting MGC32805 in a sandwich mode and inducing ΔFAS neoantigen and triggering FAS properties switch: implication in colorectal cancer.
Pre-mRNA alternative splicing (AS) is a crucial process, which plays a significant role in inducing tumor subtype-specific alterations and the hallmark of epigenetic heterogeneity in tumorigenesis. However, the regulatory mechanisms of pre-mRNA AS remain obscure. This study demonstrates that splicing factor RBM5 recruits long non-coding RNA MGC32805, and they act in concert as oncogenes in colorectal cancer (CRC) cells by preventing apoptosis, as well as promoting migration and resistance to 5-Fluorouracil (5-FU). Specifically, they promote the exclusion of exon 6 in the FAS pre-mRNA, leading to decreased expression of mFAS (an apoptotic isoform) and increased expression of ΔFAS (an anti-apoptotic isoform) in both CRC cells and a mouse xenograft model. RBM5, which contains Leu650 and Arg681 residues in the ZnF-C2H2 domain, recognizes the "GUACG" (-1299 to -1303) motif in MGC32805. Furthermore, MGC32805 blocks the binding site (Lys645) of the E3 ubiquitin ligase PRPF19, which targets RBM5 for degradation, thus increasing the stability of RBM5. The His665 and Leu668 residues of RBM5 specifically bind to the FAS exon 6 adjacent element (GAACAAA), which drives FAS-AS events and increases the expression ratio of the ΔFAS/mFAS isoforms. These findings introduce a novel research strategy to investigate the epigenetic heterogeneity and plasticity of tumorigenesis. They also shed light on the mechanism of MGC32805-mediated transformation of the FAS tumor neoantigen function from a tumor suppressor to an oncogene at the AS level through its interactions with RBM5.
期刊介绍:
Oncogene is dedicated to advancing our understanding of cancer processes through the publication of exceptional research. The journal seeks to disseminate work that challenges conventional theories and contributes to establishing new paradigms in the etio-pathogenesis, diagnosis, treatment, or prevention of cancers. Emphasis is placed on research shedding light on processes driving metastatic spread and providing crucial insights into cancer biology beyond existing knowledge.
Areas covered include the cellular and molecular biology of cancer, resistance to cancer therapies, and the development of improved approaches to enhance survival. Oncogene spans the spectrum of cancer biology, from fundamental and theoretical work to translational, applied, and clinical research, including early and late Phase clinical trials, particularly those with biologic and translational endpoints.