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SRSF3/AMOTL1 Splicing Axis Promotes the Tumorigenesis of Nasopharyngeal Carcinoma through Regulating the Nucleus Translocation of YAP1

ABSTRACT: Dysregulation of serine/arginine splicing factors (SRSFs) and thereby the abnormal alternative splicing (AS) has been widely implicated in the development of multiple cancers, but scarcely investigated in nasopharyngeal carcinoma (NPC). Here we examine the expression of 12 classical SRSFs between 87 NPC and 10 control samples, revealing a significant upregulation of SRSF3 and its association with worse prognosis in NPC. Functional assays demonstrate that SRSF3 knockdown markedly inhibits the proliferation, migration, tumorigenesis and induces apoptosis in NPC cells, suggesting its oncogenic role in NPC progression. Transcriptome analysis reveals 1 934 SRSF3-regulated AS events in genes involved in cell cycle and mRNA metabolism, among which the generation of a long isoform of AMOTL1 (AMOTL1-L) is further verified through a direct bond of SRSF3 RRM domain with the exon 12 of AMOTL1 to promote the exon inclusion. Functional studies reveal that AMOTL1-L could promote the proliferation and migration of NPC cells, nor did AMOTL1-S. Moreover, overexpression of AMOTL1-L significantly rescues the abovementioned inhibitory effects of SRSF3 knockdown, nor did AMOTL1-S. Furthermore, compared with AMOTL1-S, AMOTL1-L has a localization preference in the intracellular than the cell membrane, leading to a stronger interaction with YAP1 to promote its translocation to nucleus. Taken together, our findings identify SRSF3/AMOTL1 as a novel alternative splicing axis with pivotal roles in NPC development, which could be served as promising prognostic biomarkers and therapeutic targets of NPC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE227503 | GEO | 2023/08/21

REPOSITORIES: GEO

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