Oncogenic translation directs spliceosome dynamics revealing an integral role for SF3A3 in breast cancer
Oncogenic translation directs spliceosome dynamics revealing an integral role for SF3A3 in breast cancer
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DOI：
10.1016/j.molcel.2021.01.034
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发表时间：
2021-04-01
期刊：
影响因子：
16
通讯作者：
Bellodi, Cristian
中科院分区：
文献类型：
--
作者：
Ciesla, Maciej;Phuong Cao Thi Ngoc;Bellodi, Cristian
剪接是一个中心的RNA为基础的过程，通常改变人类癌症;然而，如何剪接体组件在肿瘤发生过程中增选仍然不清楚，在这里，我们解开核心剪接因子SF 3A 3在一个基于预防的程序，重新布线剪接在恶性转化的关系。在MYC超活化后，SF 3A 3水平以eIF 3D依赖性方式通过RNA茎环进行调节。这确保了富含线粒体调节因子的mRNA的准确剪接。改变的SF 3A 3翻译导致代谢重编程和干细胞样特性，从而在体内激发MYC致瘤潜力。我们的分析表明，SF 3A 3蛋白水平预测侵袭性人类乳腺癌的分子和表型特征。这些发现揭示了剪接和翻译之间的转录后相互作用，其控制MYC驱动的肿瘤发生的关键方面。
Splicing is a central RNA-based process commonly altered in human cancers; however, how spliceosomal components are co-opted during tumorigenesis remains poorly defined, Here we unravel the core splice factor SF3A3 at the nexus of a translation-based program that rewires splicing during malignant transformation. Upon MYC hyperactivation, SF3A3 levels are modulated translationally through an RNA stem-loop in an elF3D-dependent manner. This ensures accurate splicing of mRNAs enriched for mitochondrial regulators. Altered SF3A3 translation leads to metabolic reprogramming and stem-like properties that fuel MYC tumorigenic potential in vivo. Our analysis reveals that SF3A3 protein levels predict molecular and phenotypic features of aggressive human breast cancers. These findings unveil a post-transcriptional interplay between splicing and translation that governs critical facets of MYC-driven oncogenesis.