Department of Neuropathology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China; Tianjin Key Laboratory of Injuries, Variations and Regeneration of the Nervous System, Tianjin, China; Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin, China.
Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China.
Int J Biochem Cell Biol. 2019 Aug;113:75-86. doi: 10.1016/j.biocel.2019.06.003. Epub 2019 Jun 11.
The relevance of RNA processing has been increasingly recognized in a variety of diseases. We previously identified serine/arginine-rich splicing factor 1 (SRSF1) as an oncodriver in glioma via splicing control. However, its splicing-independent roles and mechanisms are poorly defined in glioma. In this study, by integrating the data mining of SRSF1-co-expressed genes, SRSF1-affected genes and experimental studies, we demonstrated that SRSF1 was the most highly expressed SRSF in the 9 tumor types tested, and it was a crucial cell cycle regulator in glioma. Importantly, we identified nuclear paraspeckle assembly transcript1 (NEAT1), an upregulated long non-coding RNA (lncRNA) in glioma, as a target of SRSF1. Endogenous NEAT1 inhibition resembled the effect of SRSF1 knockdown on glioma cell proliferation by retarding cell cycle. Mechanistically, we proved that SRSF1 bound to NEAT1 and facilitated its RNA stability. The positive correlation between SRSF1 and NEAT1 levels in cancers further supported the positive regulation of NEAT1 by SRSF1. Collectively, our results provide novel insights on the splicing-independent mechanisms of SRSF1 in glioma, and confirm that NEAT1, whose stability maintained by SRSF1, implicates gliomagenesis by regulating cell cycle. Both SRSF1 and NEAT1 may serve as promising targets for antineoplastic therapies.
RNA 处理的相关性在各种疾病中得到了越来越多的认识。我们之前通过剪接控制鉴定了丝氨酸/精氨酸丰富的剪接因子 1（SRSF1）是神经胶质瘤中的致癌驱动因子。然而，其在神经胶质瘤中的剪接非依赖性作用和机制尚未得到明确界定。在这项研究中，我们通过整合 SRSF1 共表达基因、受 SRSF1 影响的基因的数据分析以及实验研究，证明 SRSF1 是所测试的 9 种肿瘤类型中表达最高的 SRSF，并且是神经胶质瘤中关键的细胞周期调节剂。重要的是，我们确定了核斑点组装转录物 1（NEAT1），即神经胶质瘤中上调的长非编码 RNA（lncRNA），是 SRSF1 的靶标。内源性 NEAT1 抑制通过延缓细胞周期类似于 SRSF1 敲低对神经胶质瘤细胞增殖的作用。从机制上讲，我们证明了 SRSF1 与 NEAT1 结合并促进其 RNA 稳定性。癌症中 SRSF1 和 NEAT1 水平之间的正相关性进一步支持了 NEAT1 受 SRSF1 的正向调节。总之，我们的研究结果为 SRSF1 在神经胶质瘤中的剪接非依赖性机制提供了新的见解，并证实了 NEAT1 的稳定性由 SRSF1 维持，通过调节细胞周期参与神经胶质瘤发生。SRSF1 和 NEAT1 都可能成为抗肿瘤治疗的有前途的靶点。
