AL398, a Novel NSUN6 Inhibitor, Attenuates Epithelial‑Mesenchymal Transition and Metastasis in Endometrial Cancer by Abrogating m5C‑Dependent Stabilization of Snail mRNA

Rákkutatás · Endometrial cancer

NSUN6 enhances epithelial‑mesenchymal transition in endometrial cancer by methylating Snail mRNA to increase its stability.

Endometrial cancer (EC) constitutes a leading gynecologic malignancy for which advanced or metastatic disease presents limited therapeutic options. The m5C methyltransferase NSUN6 is significantly upregulated in EC tissues and correlates with higher tumor grade and unfavorable prognosis. Functional studies employing gain‑ and loss‑of‑function models revealed that NSUN6 specifically enhances EC cell migration and invasion both in vitro and in vivo, without altering proliferation or apoptosis. Mechanistically, NSUN6 drives EMT by catalyzing m5C modification on Snail mRNA, which stabilizes the transcript of this key EMT transcription factor. AL398 was identified as a novel small‑molecule inhibitor that binds potently to the NSUN6 active site and suppresses its methyltransferase activity. Treatment with AL398 effectively inhibited the NSUN6/m5C/Snail axis, reversed the EMT phenotype, and attenuated EC cell migration, invasion, and metastasis in preclinical models.

NSUN6 represents a novel target for therapeutic intervention in metastatic endometrial cancer, and the small‑molecule inhibitor AL398 provides a proof‑of‑concept for RNA‑methylation‑targeted therapy.

Bizonyítékszint: Sejtvonalas. Laboratóriumi sejtekben vizsgálták.

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