STC2 promotes cisplatin resistance through metabolic reprogramming and lactylation-mediated epigenetic regulation in cervical cancer.

Abstract

Cervical cancer (CC) is a major threat to women's health globally, and the development of cisplatin (DDP) resistance is a key factor leading to treatment failure. Prior research from our group has demonstrated the significant involvement of stanniocalcin-2 (STC2) in mediating DDP-resistance in CC. This study explores the role of STC2 in promoting chemoresistance through metabolic and epigenetic reprogramming. We find that STC2 is significantly upregulated in SiHa/DDP cells, a DDP-resistant subline of SiHa, where it enhances the malignant phenotype and drives glycolytic metabolism, increasing lactate production. The accumulated lactate subsequently elevates global histone lactylation, notably at the H3K18la site. Integrated CUT&Tag and RNA-seq analyses identify RBM20 as a potential downstream target of H3K18la-mediated transcriptional activation. Knockdown of STC2 reverses these effects, promoting chemosensitivity to DDP. Our results unveil a novel STC2/glycolysis/lactylation/RBM20 axis underlying DDP resistance in CC, providing new insights into potential therapeutic strategies to overcome chemoresistance by targeting this pathway.