Division of Molecular Hematology, Department of Laboratory Medicine, Lund Stem Cell Center, Faculty of Medicine, Lund University, 22184 Lund, Sweden.
Division of Translational Cancer Research, Department of Laboratory Medicine, Faculty of Medicine, Lund University, 22363 Lund, Sweden.
Mol Cell. 2021 Apr 1;81(7):1453-1468.e12. doi: 10.1016/j.molcel.2021.01.034. Epub 2021 Mar 3.
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 eIF3D-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.
剪接是一种常见的基于 RNA 的过程，在人类癌症中经常发生改变；然而，剪接体成分在肿瘤发生过程中是如何被募集的仍不清楚。在这里，我们在一个基于翻译的程序的交汇点上解开了核心剪接因子 SF3A3 的秘密，该程序在恶性转化过程中重新布线剪接。在 MYC 过度激活后，SF3A3 水平通过 eIF3D 依赖性的 RNA 茎环在翻译水平上进行调节。这确保了富含线粒体调节剂的 mRNA 的准确剪接。SF3A3 翻译的改变导致代谢重编程和干细胞样特性，从而在体内为 MYC 致癌潜能提供动力。我们的分析表明，SF3A3 蛋白水平预测了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一种转录后相互作用，它控制着 MYC 驱动的致癌作用的关键方面。
