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

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.

GSDMA/Gasdermin A; MET/mesenchymal–epithelial transition; Oxaliplatin; RBM47; chemoresistance; colorectal cancer; pyroptosis.