# A new candidate tumor suppressor tRF-Ser inhibits gastric cancer progression by regulating the CNBP/HSPA8 axis

## TL;DR

A new small RNA called tRF-Ser was found to suppress gastric cancer by regulating a key protein pathway, offering potential for new treatments.

## Contribution

The discovery of tRF-Ser as a tumor suppressor and its regulatory mechanism involving the CNBP/HSPA8 axis in gastric cancer.

## Key findings

- tRF-Ser is significantly downregulated in gastric cancer tissues and cell lines.
- tRF-Ser inhibits cancer progression by inducing ferroptosis and suppressing EMT.
- tRF-Ser interacts with CNBP to regulate HSPA8 and β-catenin signaling.

## Abstract

Gastric cancer (GC) is a highly aggressive malignancy with a poor prognosis. Transfer RNA-derived small RNAs (tsRNAs) are implicated in tumorigenesis, but their precise mechanistic roles in GC progression remain incompletely understood. We performed high-throughput sequencing in four paired GC/normal tissues to profile tsRNAs. The functional and mechanistic role of a candidate tsRNA was systematically investigated, alongside a suite of techniques including fluorescence in situ hybridization, RNA immunoprecipitation, RNA pull-down, chromatin immunoprecipitation, and luciferase reporter assays. We identified a novel tsRNA, tRF-Ser, that was significantly downregulated in GC tissues and cell lines, and its expression was correlated with favorable survival. Functionally, tRF-Ser acted as a tumor suppressor by inhibiting epithelial-mesenchymal transition (EMT), inducing ferroptosis, and enhancing sensitivity to 5-fluorouracil chemotherapy. Mechanistically, tRF-Ser directly bound to the cellular nucleic acid-binding protein CNBP (a transcription factor), promoting its accumulation in the cytoplasm and preventing its binding to the HSPA8 promoter to downregulate HSPA8. Then, the tRF-Ser/CNBP/HSPA8 axis suppressed EMT by inhibiting β-catenin nuclear translocation and promoted ferroptosis by facilitating STUB1-mediated ubiquitination degradation of GPX4. Our study unveils that the tRF-Ser/CNBP/HSPA8 axis may constrain GC progression by regulating energy metabolism, which highlights the therapeutic potential of targeting this axis for GC treatment.