State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, Yunnan, China.
Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, 650201, China.
Cell Death Dis. 2022 May 3;13(5):428. doi: 10.1038/s41419-022-04867-w.
Alternative splicing (AS) is a promising clinical target for cancer treatment at the post-transcriptional level. We previously identified a unique AS profile in triple-negative breast cancer (TNBC), which is regulated by the splicing regulator TAR DNA-binding protein-43 (TDP43), thus indicating the crucial role of TDP43 in heterogeneous TNBC. Cluster of differentiation 44 (CD44), a widely recognized marker for breast cancer stem cells (BCSCs), is extensively spliced into CD44 variant AS isoforms (CD44v) during the development of breast cancer. At present, however, the regulatory mechanism of CD44v is not fully understood. In the current study, we found that loss of TDP43 inhibits BCSC stemness by reducing the abundance of CD44v. In addition, serine-arginine-rich splicing factor 3 (SRSF3), another splicing factor and partner of TDP43, acts as an upstream regulator of TDP43 to maintain CD44v isoforms and thereafter BCSC stemness. Mechanistically, SRSF3 stabilizes the mRNA of TDP43 by inhibiting nonsense-mediated decay (NMD). These findings illustrate the important role of complicated regulatory networks formed by splicing factors in TNBC progression, thus providing potential therapeutic targets from an AS perspective.
选择性剪接（AS）是一种有前途的癌症治疗靶点，可在转录后水平发挥作用。我们之前在三阴性乳腺癌（TNBC）中发现了一种独特的 AS 谱，其受剪接调节因子 TAR DNA 结合蛋白 43（TDP43）调控，这表明 TDP43 在异质性 TNBC 中发挥着关键作用。CD44 是乳腺癌干细胞（BCSCs）的一个广泛认可的标志物，在乳腺癌的发展过程中，CD44 广泛剪接为 CD44 变体 AS 异构体（CD44v）。然而，目前 CD44v 的调控机制尚不完全清楚。在本研究中，我们发现 TDP43 的缺失通过降低 CD44v 的丰度来抑制 BCSC 干性。此外，另一个剪接因子 SRSF3 是 TDP43 的伴侣，也是 SRSF3 作为 TDP43 的上游调节剂，维持 CD44v 异构体，进而维持 BCSC 干性。从机制上讲，SRSF3 通过抑制无意义介导的降解（NMD）来稳定 TDP43 的 mRNA。这些发现说明了剪接因子形成的复杂调控网络在 TNBC 进展中的重要作用，从而从 AS 角度提供了潜在的治疗靶点。
