RNA G-quadruplexes cause eIF4A-dependent oncogene translation in cancer

The translational control of oncoprotein expression is implicated in many cancers. Here we report an eIF4A/DDX2 RNA helicase-dependent mechanism of translational control that contributes to oncogenesis and underlies the anticancer effects of Silvestrol and related compounds. For example, eIF4A promotes T-ALL development in vivo and is required for leukaemia maintenance. Accordingly, inhibition of eIF4A with Silvestrol has powerful therapeutic effects in vitro and in vivo. We use transcriptome-scale ribosome footprinting to identify the hallmarks of eIF4A-dependent transcripts. These include 5'UTR sequences such as the 12-mer guanine quartet (CGG)4 motif that can form RNA G-quadruplex structures. Notably, among the most eIF4A-dependent and Silvestrol-sensitive transcripts are a number of oncogenes, super-enhancer associated transcription factors, and epigenetic regulators. Hence, the 5'UTRs of selected cancer genes harbour a targetable requirement for the eIF4A RNA helicase. Comparison of ribosome-protected RNA for drug treated and DMSO treated KOPT-K1 cell, two replicates of ribosome-protected RNA sequencing and three replicates of RNA-seq.

癌蛋白表达的翻译调控与多种癌症的发生发展密切相关。本研究报道了一种依赖eIF4A/DDX2 RNA解旋酶（RNA helicase）的翻译调控机制，该机制可促进肿瘤发生，同时也是Silvestrol及其相关化合物发挥抗癌作用的核心基础。例如，eIF4A可在体内促进T细胞急性淋巴细胞白血病（T-ALL）的发生发展，且对白血病细胞的维持至关重要。因此，使用Silvestrol抑制eIF4A活性，在体外与体内均展现出强效的治疗效果。我们采用转录组范围的核糖体足迹测序（ribosome footprinting）技术，鉴定出依赖eIF4A的转录本的特征标记。这些特征包含5'非翻译区（5'UTR）序列，例如可形成RNA G-四链体结构的12聚体鸟嘌呤四重态（CGG）4基序。值得注意的是，在最依赖eIF4A且对Silvestrol敏感的转录本中，包含多种癌基因、超级增强子相关转录因子以及表观遗传调控因子。因此，部分癌症基因的5'UTR存在可被靶向调控的eIF4A RNA解旋酶依赖需求。本研究对药物处理与二甲基亚砜（DMSO）处理的KOPT-K1细胞的核糖体保护RNA进行比较分析，其中核糖体足迹测序设置2次生物学重复，RNA测序设置3次生物学重复。