Division of Cancer Genome Research, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
Faculty of Biosciences, Heidelberg University, Heidelberg, Germany.
Mol Cancer Res. 2020 Oct;18(10):1545-1559. doi: 10.1158/1541-7786.MCR-20-0021. Epub 2020 Jul 9.
Numerous noncoding transcripts have been reported to correlate with cancer development and progression. Nevertheless, there remains a paucity of long noncoding RNAs (lncRNA) with well-elucidated functional roles. Here, we leverage the International Cancer Genome Consortium-Early Onset Prostate Cancer transcriptome and identify the previously uncharacterized lncRNA to be upregulated in prostate tumors. Phenotypic characterization of revealed its positive impact on cellular proliferation, colony formation, and migration. We demonstrate that transcription is directly activated by ERG, an oncogenic transcription factor overexpressed in 50% of prostate cancers. Chromatin isolation by RNA purification-mass spectrometry revealed the interaction of with the 14-3-3ε protein, leading to enhanced sequestration of tumor suppressive FOXO1. Altogether, our results provide a rationale on how ERG overexpression, partly by driving transcription, could confer survival advantage to prostate cancer cells and potentially prime PTEN-intact prostate cells for cellular transformation through FOXO inactivation. IMPLICATIONS: The study describes a novel lncRNA-mediated mechanism of regulating the FOXO signaling pathway and provides additional insight into the role of ERG in prostate cancer cells.
大量的非编码转录本已被报道与癌症的发生和发展相关。然而，具有明确功能作用的长非编码 RNA（lncRNA）仍然很少。在这里，我们利用国际癌症基因组联合会-早发性前列腺癌转录组，鉴定出以前未被描述的 lncRNA 在前列腺肿瘤中上调。对 的表型特征分析表明，它对细胞增殖、集落形成和迁移有积极影响。我们证明，转录因子 ERG（一种在 50%的前列腺癌中过表达的致癌转录因子）可直接激活 。RNA 纯化-质谱法的染色质分离揭示了 与 14-3-3ε 蛋白的相互作用，导致肿瘤抑制因子 FOXO1 的封闭增强。总之，我们的研究结果提供了一个合理的机制，说明 ERG 过表达如何通过驱动 转录，为前列腺癌细胞提供生存优势，并通过 FOXO 失活使 PTEN 完整的前列腺细胞潜在地为细胞转化做好准备。意义：该研究描述了一种新的 lncRNA 调节 FOXO 信号通路的机制，并为 ERG 在前列腺癌细胞中的作用提供了更多的见解。
