# RBM47-Induced Gasdermin A/GSDMA Mediates Mesenchymal–Epithelial Transition and Pyroptosis of Colorectal Cancer Cells

## TL;DR

This study shows that RBM47 suppresses colorectal cancer by stabilizing GSDMA mRNA, promoting cell death and chemotherapy sensitivity.

## Contribution

Identifies GSDMA as a novel downstream effector of RBM47 in tumor suppression and chemotherapy response.

## Key findings

- RBM47 stabilizes GSDMA mRNA, leading to increased GSDMA expression and mesenchymal-to-epithelial transition.
- Activation of the RBM47/GSDMA axis triggers pyroptosis and enhances sensitivity to Oxaliplatin in CRC cells.
- RBM47 expression correlates with better chemotherapy response in CRC patients.

## Abstract

The RNA-binding motif protein 47 (RBM47) is an RNA-binding protein that is frequently down-regulated in colorectal cancer (CRC). This study addresses a significant gap in understanding how RBM47 mediates tumor suppression, as prior studies had established RBM47 as an antagonist of epithelial-to-mesenchymal transition/EMT and metastasis, but had not pinpointed its critical effectors. Here, we identified GSDMA as a key RBM47 target. Binding of RBM47 stabilized the GSDMA mRNA, resulting in elevated levels of GSDMA mRNA and protein. GSDMA mediated the RBM47-induced mesenchymal-to-epithelial transition/MET, as well as suppression of migration and invasion. Furthermore, activation of the RBM47/GSDMA regulatory connection triggered pyroptosis, a type of programmed cell death. Notably, the RBM47/GSDMA axis sensitized CRC cells to the chemotherapeutic Oxaliplatin. In CRC patients, elevated RBM47 expression was associated with a better response to FOLFOX chemotherapy, highlighting this pathway as a potential predictive biomarker for responsiveness to chemotherapy.

Down-regulation of the RNA-binding motif protein 47 (RBM47) frequently occurs in colorectal cancer (CRC) and is associated with poor prognosis. However, the downstream effectors of RBM47 have remained unknown. Therefore, we performed a comprehensive RNA-Seq analysis after inactivation or ectopic expression of RBM47. Gasdermin A/GSDMA, a poorly characterized member of the gasdermin family highly expressed in gastrointestinal epithelium, was identified as the most differentially regulated transcript. RBM47 directly bound to the 3′-untranslated region of GSDMA mRNA and stabilized it. Consistently, ectopic RBM47 increased GSDMA mRNA and protein expression, whereas RBM47 knockdown had the opposite effect. GSDMA was necessary for the RBM47-induced mesenchymal-to-epithelial transition (MET) and suppression of migration and invasion by RBM47 in CRC cells. Moreover, activation of the RBM47/GSDMA axis triggered pyroptosis, a form of cell death characterized by cell swelling, plasma membrane rupture, and, therefore, immunogenic effects. Both RBM47 and GSDMA enhanced sensitivity to Oxaliplatin through the induction of MET and pyroptosis. Knockdown of GSDMA abolished RBM47-mediated pyroptosis and chemo-sensitization. Analysis of CRC patient cohorts revealed that RBM47 expression correlates with response to FOLFOX chemotherapy. Therefore, our results establish GSDMA as a critical downstream mediator of RBM47-induced tumor suppression that links epithelial differentiation and pyroptosis to chemotherapy sensitivity. Finally, these findings identify the RBM47/GSDMA axis as a potential predictive biomarker for the response to Oxaliplatin in CRC patients.