Background RNA-binding proteins (RBPs) function as master regulators of gene expression. Alterations in RBP expression and function are often observed in cancer and influence critical pathways implicated in tumor initiation and growth. Identification and characterization of oncogenic RBPs and their regulatory networks provide new opportunities for targeted therapy. Results We identify the RNA-binding protein SERBP1 as a novel regulator of glioblastoma (GBM) development. High SERBP1 expression is prevalent in GBMs and correlates with poor patient survival and poor response to chemo- and radiotherapy. SERBP1 knockdown causes delay in tumor growth and impacts cancer-relevant phenotypes in GBM and glioma stem cell lines. RNAcompete identifies a GC-rich region as SERBP1-binding motif; subsequent genomic and functional analyses establish SERBP1 regulation role in metabolic routes preferentially used by cancer cells. An important consequence of these functions is SERBP1 impact on methionine production. SERBP1 knockdown decreases methionine levels causing a subsequent reduction in histone methylation as shown for H3K27me3 and upregulation of genes associated with neurogenesis, neuronal differentiation, and function. Further analysis demonstrates that several of these genes are downregulated in GBM, potentially through epigenetic silencing as indicated by the presence of H3K27me3 sites. Conclusions SERBP1 is the first example of an RNA-binding protein functioning as a central regulator of cancer metabolism and indirect modulator of epigenetic regulation in GBM. By bridging these two processes, SERBP1 enhances glioma stem cell phenotypes and contributes to GBM poorly differentiated state.

中文翻译：

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RNA结合蛋白SERBP1通过桥接癌症代谢和表观遗传调控，在胶质母细胞瘤中发挥新型致癌因子的作用


背景 RNA 结合蛋白 (RBP) 作为基因表达的主要调节因子。 RBP 表达和功能的改变经常在癌症中观察到，并影响与肿瘤发生和生长有关的关键途径。致癌 RBP 及其调控网络的鉴定和表征为靶向治疗提供了新的机会。结果我们确定 RNA 结合蛋白 SERBP1 是胶质母细胞瘤 (GBM) 发展的新型调节因子。 SERBP1 高表达在 GBM 中普遍存在，与患者生存率低以及对化疗和放疗的反应不佳相关。 SERBP1 敲低会导致肿瘤生长延迟，并影响 GBM 和神经胶质瘤干细胞系中与癌症相关的表型。 RNAcompete 将富含 GC 的区域识别为 SERBP1 结合基序；随后的基因组和功能分析确定了 SERBP1 在癌细胞优先使用的代谢途径中的调节作用。这些功能的一个重要结果是 SERBP1 对蛋氨酸产生的影响。 SERBP1 敲除降低了蛋氨酸水平，导致随后的组蛋白甲基化减少（如 H3K27me3 所示）以及与神经发生、神经元分化和功能相关的基因上调。进一步的分析表明，其中一些基因在 GBM 中下调，可能是通过表观遗传沉默（H3K27me3 位点的存在表明）。结论 SERBP1 是第一个 RNA 结合蛋白作为癌症代谢的中央调节剂和 GBM 表观遗传调控的间接调节剂的例子。通过桥接这两个过程，SERBP1 增强了神经胶质瘤干细胞表型，并导致 GBM 低分化状态。