NAT10 Phase Separation Regulates YTHDF1 Splicing to Promote Gastric Cancer Progression.

Clicks: 136
ID: 280147
2024
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Abstract
Gastric cancer (GC) is an aggressive malignancy with poor patient outcomes. NAT10 is an acetyltransferase that has been reported to contribute to GC progression. In-depth investigation into the underlying molecular mechanisms driven by NAT10 could help identify therapeutic targets to improve GC treatment. Here, we found that NAT10 forms condensates to regulate RNA dynamics and promote GC progression. In GC patient samples, elevated NAT10 expression correlated with an unfavorable prognosis, advanced disease stage, and metastasis. NAT10 enhanced proliferation, migration, and invasion of GC cells, supported growth of patient-derived organoids, and accelerated tumor development. A C-terminal intrinsically disordered region mediated liquid-liquid phase separation (LLPS) of NAT10 and was essential for its tumor-promoting function in GC. Moreover, NAT10 interacted with the splicing factor SRSF2, leading to its acetylation and increased stability. Acetylated SRSF2 directly bound to the pre-mRNA of the m6A reader YTHDF1, resulting in enhanced YTHDF1 exon 4 skipping and upregulation of a short YTHDF1 transcript that could stimulate GC cell proliferation and migration. Furthermore, YTHDF1 exon 4 skipping correlated with NAT10 and SRSF2 expression and was associated with a more aggressive phenotype in GC patient samples. Together, this study uncovers the role of NAT10 LLPS in modulating YTHDF1 splicing through SRSF2 acetylation to drive GC progression, providing insights into the oncogenic mechanism of NAT10.
Reference Key
liu2024nat10cancer Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Liu, Songyi;Lin, Chunlin;Lin, Xiang;Lin, Penghang;He, Ruofan;Pan, Xiaoyu;Lin, Yan;Ye, Jianxin;Zhu, Guangwei;
Journal Cancer research
Year 2024
DOI
10.1158/0008-5472.CAN-23-4062
URL
Keywords
Autoimmune Diseases inflammation autoimmunity innate immunity adaptive immunity

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