Department of Life Sciences, University of Modena and Reggio Emilia, via Campi 213/D, 41125 Modena, Italy.
Cells. 2020 Mar 20;9(3):760. doi: 10.3390/cells9030760.
Alternative splicing (AS) is a finely regulated mechanism for transcriptome and proteome diversification in eukaryotic cells. Correct balance between AS isoforms takes part in molecular mechanisms that properly define spatiotemporal and tissue specific transcriptional programs in physiological conditions. However, several diseases are associated to or even caused by AS alterations. In particular, multiple AS changes occur in cancer cells and sustain the oncogenic transcriptional program. Transcription factors (TFs) represent a key class of proteins that control gene expression by direct binding to DNA regulatory elements. AS events can generate cancer-associated TF isoforms with altered activity, leading to sustained proliferative signaling, differentiation block and apoptosis resistance, all well-known hallmarks of cancer. In this review, we focus on how AS can produce TFs isoforms with opposite transcriptional activities or antagonistic functions that severely impact on cancer biology. This summary points the attention to the relevance of the analysis of TFs splice variants in cancer, which can allow patients stratification despite the presence of interindividual genetic heterogeneity. Recurrent TFs variants that give advantage to specific cancer types not only open the opportunity to use AS transcripts as clinical biomarkers but also guide the development of new anti-cancer strategies in personalized medicine.
可变剪接（AS）是真核细胞转录组和蛋白质组多样化的一种精细调控机制。正确平衡 AS 异构体参与了分子机制，在生理条件下适当定义时空和组织特异性转录程序。然而，有几种疾病与 AS 改变有关，甚至是由其引起的。特别是，癌细胞中会发生多种 AS 变化，并维持致癌转录程序。转录因子（TFs）是一类通过直接结合 DNA 调控元件来控制基因表达的关键蛋白。AS 事件可产生具有改变活性的癌症相关 TF 异构体，导致持续的增殖信号、分化阻滞和凋亡抵抗，这些都是癌症的典型特征。在这篇综述中，我们重点关注 AS 如何产生具有相反转录活性或拮抗功能的 TF 异构体，这些异构体严重影响癌症生物学。这一总结强调了分析癌症中 TF 剪接变异体的重要性，尽管存在个体间遗传异质性，但这可以允许对患者进行分层。赋予特定癌症类型优势的反复出现的 TF 变体不仅为将 AS 转录本用作临床生物标志物开辟了机会，而且还为个性化医学中的新型抗癌策略的发展提供了指导。
