Zhao Haiping, Wu Nana, Wei Gaigai, Zhang Huiling, Ren Tingrong, Yi Jingjing, Zhang Yuqi, Wang Zixi, Wang Yihan, Guo Zhihan, Zhang Duanwu
Children's Hospital of Fudan University, National Children's Medical Center, and Shanghai Key Laboratory of Medical Epigenetics, International Colaboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
Front Immunol. 2024 Dec 4;15:1474527. doi: 10.3389/fimmu.2024.1474527. eCollection 2024.
RNA splicing is a crucial posttranscriptional process that governs gene expression, and defects in alternative splicing contribute to various diseases, including cancer. Tumor suppressing subtransferable candidate 4 (TSSC4) is a known tumor suppressor and has been identified as part of the U5 small nuclear ribonucleoprotein (snRNP), which is involved in tri-snRNP biogenesis. However, the precise role of TSSC4 in regulating alternative splicing and its impact on tumor growth remain unclear.
To explore the link between splicing modulation and tumor suppression driven by TSSC4, we conducted transcriptome sequencing (RNA-seq) on TSSC4-knockout and wild-type HeLa cells. Additionally, we analyzed alternative splicing and gene expression in various cancer cell lines, including TSSC4-knockout A549 cells and TSSC4-knockdown PANC-1, MDA-MB-231, and MCF-7 cells. Splicing patterns and gene expression profiles were compared between TSSC4-deficient and control cells.
Our RNA-seq analysis revealed that TSSC4 deficiency in HeLa cells results in widespread alterations in splicing patterns and gene expression. Specifically, the loss of TSSC4 led to abnormal alternative splicing events and dysregulation of tumor-associated genes, including several oncogenes. This effect was confirmed across multiple cancer cell lines, highlighting a consistent role of TSSC4 in splicing regulation.
These findings demonstrate that TSSC4 plays a crucial role in regulating RNA splicing, particularly in controlling the splicing of many oncogenes. Our results reveal a novel mechanism by which TSSC4 mediates tumor suppression through the modulation of alternative splicing, which could provide implications for understanding TSSC4's role in cancer biology.
RNA剪接是一种关键的转录后过程，它调控基因表达，而可变剪接缺陷会导致包括癌症在内的多种疾病。肿瘤抑制性亚可转移候选物4（TSSC4）是一种已知的肿瘤抑制因子，已被鉴定为U5小核核糖核蛋白（snRNP）的一部分，该蛋白参与三snRNP生物发生。然而，TSSC4在调节可变剪接中的精确作用及其对肿瘤生长的影响仍不清楚。
为了探究由TSSC4驱动的剪接调控与肿瘤抑制之间的联系，我们对TSSC4基因敲除和野生型HeLa细胞进行了转录组测序（RNA-seq）。此外，我们分析了多种癌细胞系中的可变剪接和基因表达，包括TSSC4基因敲除的A549细胞以及TSSC4基因敲低的PANC-1、MDA-MB-231和MCF-7细胞。比较了TSSC4缺陷细胞和对照细胞之间的剪接模式和基因表达谱。
我们的RNA-seq分析表明，HeLa细胞中TSSC4的缺陷导致剪接模式和基因表达的广泛改变。具体而言，TSSC4的缺失导致异常的可变剪接事件以及包括多个癌基因在内的肿瘤相关基因的失调。这种效应在多个癌细胞系中得到证实，突出了TSSC4在剪接调控中的一致作用。
这些发现表明TSSC4在调节RNA剪接中起关键作用，特别是在控制许多癌基因的剪接方面。我们的结果揭示了一种新机制，即TSSC4通过调节可变剪接来介导肿瘤抑制，这可能为理解TSSC4在癌症生物学中的作用提供启示。
