The snoRNA SNORA21 promotes gastric tumorigenesis by attenuating P53 activity through CHK1 phosphorylation inhibition and PERP-dependent feedback loops.

Small nucleolar RNAs (snoRNAs) have emerged as critical regulators in cancer progression, yet their mechanistic roles in gastric cancer (GC) remain poorly understood. Here, we identify SNORA21 as an oncogenic snoRNA that drives GC pathogenesis through P53 pathway inactivation. We demonstrated significant SNORA21 upregulation in GC tissues and cell lines compared to normal controls. Functional studies revealed that SNORA21 knockdown inhibited tumor growth, while its overexpression promoted malignant phenotypes, establishing its crucial role in determining GC cell fate. Transcriptomic profiling and mechanistic investigations uncovered that SNORA21 represses P53 tumor suppressor activity through a novel CHK1-dependent mechanism. Specifically, SNORA21 attenuated DNA damage responses by inhibiting CHK1 phosphorylation, thereby preventing P53 activation. Remarkably, SNORA21 depletion triggered PERP induction - a P53 effector - which formed a positive feedback loop by suppressing MDM2-mediated P53 degradation. This dual regulatory mechanism (CHK1 inhibition and PERP-MDM2 feedback) explains how SNORA21 sustains P53 inactivation in GC cells. In vivo xenograft models confirmed that SNORA21 silencing suppressed tumor growth while enhancing P53 signaling activity. Our work not only elucidates SNORA21 as a master regulator of the P53 pathway in GC but also reveals its therapeutic potential. The discovery of the SNORA21-CHK1-PERP-MDM2 axis provides a conceptual framework for targeting snoRNA-mediated P53 regulation in GC treatment. These findings position SNORA21 as both a prognostic biomarker and a candidate for RNA-based therapeutics in P53-wildtype gastric cancers.