Loss of CSDE1 Function Enhances mRNA Stability of Interleukin-6 and Promotes Malignant Transformation in Endometrial Cancer Cells.

CSDE1 (cold shock domain-containing protein E1) is an RNA-binding protein that plays a critical role in regulating mRNA stability and translation. Previous studies suggest that CSDE1 is downregulated or mutated in various cancers, including endometrial cancer (EC), but its exact role in tumor progression remains unclear. In this study, we demonstrate that the loss of CSDE1 function promotes malignant transformation in EC cells by enhancing the stability of interleukin-6 (IL-6) mRNA. Using data from The Cancer Genome Atlas (TCGA), we show that CSDE1 is frequently mutated and significantly reduced in EC tissues. CSDE1 depletion in EC cell lines using CRISPR-Cas9-mediated knockout (KO) significantly increases cell proliferation, migration, and invasion, and induced epithelial-to-mesenchymal transition (EMT). Transcriptomic analysis reveals robust mRNA upregulation of IL-6, a cytokine known to drive inflammation and tumor progression. We show that CSDE1 directly interacts with IL-6 mRNA and CSDE1 loss stabilizes IL-6 mRNA. Functionally, silencing IL-6 or inhibiting its signaling with siltuximab reverse the malignant phenotypes induced by CSDE1 knockout. These findings identify CSDE1 as a tumor suppressor in EC and uncover a novel CSDE1–IL-6 regulatory axis that drives tumor progression, positioning IL-6 as a potential therapeutic target in CSDE1-deficient EC.