Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada; McGill University and Genome Quebec Innovation Centre, Montreal, QC H3A 0G1, Canada.
Department of Pathology, McGill University, Montreal, QC H3A 2B4, Canada.
Cell Rep. 2018 May 8;23(6):1639-1650. doi: 10.1016/j.celrep.2018.04.031.
Widespread remodeling of the transcriptome is a signature of cancer; however, little is known about the post-transcriptional regulatory factors, including RNA-binding proteins (RBPs) that regulate mRNA stability, and the extent to which RBPs contribute to cancer-associated pathways. Here, by modeling the global change in gene expression based on the effect of sequence-specific RBPs on mRNA stability, we show that RBP-mediated stability programs are recurrently deregulated in cancerous tissues. Particularly, we uncovered several RBPs that contribute to the abnormal transcriptome of renal cell carcinoma (RCC), including PCBP2, ESRP2, and MBNL2. Modulation of these proteins in cancer cell lines alters the expression of pathways that are central to the disease and highlights RBPs as driving master regulators of RCC transcriptome. This study presents a framework for the screening of RBP activities based on computational modeling of mRNA stability programs in cancer and highlights the role of post-transcriptional gene dysregulation in RCC.
转录组的广泛重构是癌症的一个特征；然而，人们对包括 RNA 结合蛋白（RBPs）在内的转录后调控因子知之甚少，这些因子调节 mRNA 的稳定性，以及 RBPs 在多大程度上有助于与癌症相关的途径。在这里，我们通过基于序列特异性 RBPs 对 mRNA 稳定性的影响来模拟基因表达的全局变化，表明 RBP 介导的稳定性程序在癌组织中经常失调。特别是，我们发现了几个 RBPs 有助于肾细胞癌（RCC）的异常转录组，包括 PCBP2、ESRP2 和 MBNL2。在癌细胞系中调节这些蛋白质会改变疾病中心的途径的表达，并强调 RBPs 是 RCC 转录组的主要调控因子。这项研究提出了一种基于癌症中 mRNA 稳定性程序的计算建模来筛选 RBP 活性的框架，并强调了转录后基因失调在 RCC 中的作用。
