RBBP6 maintains glioblastoma stem cells through CPSF3-dependent alternative polyadenylation.

IF 13 1区 生物学 Q1 CELL BIOLOGY Cell Discovery Pub Date : 2024-03-19 DOI:10.1038/s41421-024-00654-3
Peng Lin, Wenyan Chen, Zhilin Long, Jichuan Yu, Jiayao Yang, Zhen Xia, Qiulian Wu, Xinyu Min, Jing Tang, Ya Cui, Fuyi Liu, Chun Wang, Jian Zheng, Wei Li, Jeremy N Rich, Lei Li, Qi Xie
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Abstract

Glioblastoma is one of the most lethal malignant cancers, displaying striking intratumor heterogeneity, with glioblastoma stem cells (GSCs) contributing to tumorigenesis and therapeutic resistance. Pharmacologic modulators of ubiquitin ligases and deubiquitinases are under development for cancer and other diseases. Here, we performed parallel in vitro and in vivo CRISPR/Cas9 knockout screens targeting human ubiquitin E3 ligases and deubiquitinases, revealing the E3 ligase RBBP6 as an essential factor for GSC maintenance. Targeting RBBP6 inhibited GSC proliferation and tumor initiation. Mechanistically, RBBP6 mediated K63-linked ubiquitination of Cleavage and Polyadenylation Specific Factor 3 (CPSF3), which stabilized CPSF3 to regulate alternative polyadenylation events. RBBP6 depletion induced shortening of the 3'UTRs of MYC competing-endogenous RNAs to release miR-590-3p from shortened UTRs, thereby decreasing MYC expression. Targeting CPSF3 with a small molecular inhibitor (JTE-607) reduces GSC viability and inhibits in vivo tumor growth. Collectively, RBBP6 maintains high MYC expression in GSCs through regulation of CPSF3-dependent alternative polyadenylation, providing a potential therapeutic paradigm for glioblastoma.

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RBBP6通过依赖CPSF3的替代多腺苷酸化来维持胶质母细胞瘤干细胞。
胶质母细胞瘤是最致命的恶性癌症之一,具有惊人的瘤内异质性,胶质母细胞瘤干细胞(GSCs)是肿瘤发生和治疗耐药性的原因之一。目前正在开发泛素连接酶和去泛素酶的药理调节剂,以治疗癌症和其他疾病。在这里,我们针对人类泛素 E3 连接酶和去泛素化酶进行了平行的体外和体内 CRISPR/Cas9 基因敲除筛选,发现 E3 连接酶 RBBP6 是维持 GSC 的重要因子。靶向RBBP6可抑制GSC的增殖和肿瘤的发生。从机制上讲,RBBP6介导了与K63连接的裂解和多腺苷酸化特异因子3(CPSF3)泛素化,从而稳定了CPSF3以调节替代性多腺苷酸化事件。RBBP6耗竭会诱导MYC竞争性内源性RNA的3'UTR缩短,从缩短的UTR中释放出miR-590-3p,从而降低MYC的表达。用小分子抑制剂(JTE-607)靶向 CPSF3 可降低 GSC 的存活率并抑制体内肿瘤生长。总之,RBBP6通过调控依赖于CPSF3的替代多腺苷酸化来维持GSC中MYC的高表达,为胶质母细胞瘤提供了一个潜在的治疗范例。
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来源期刊
Cell Discovery
Cell Discovery Biochemistry, Genetics and Molecular Biology-Molecular Biology
CiteScore
24.20
自引率
0.60%
发文量
120
审稿时长
20 weeks
期刊介绍: Cell Discovery is a cutting-edge, open access journal published by Springer Nature in collaboration with the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences (CAS). Our aim is to provide a dynamic and accessible platform for scientists to showcase their exceptional original research. Cell Discovery covers a wide range of topics within the fields of molecular and cell biology. We eagerly publish results of great significance and that are of broad interest to the scientific community. With an international authorship and a focus on basic life sciences, our journal is a valued member of Springer Nature's prestigious Molecular Cell Biology journals. In summary, Cell Discovery offers a fresh approach to scholarly publishing, enabling scientists from around the world to share their exceptional findings in molecular and cell biology.
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