HDAC4 super-enhancer drives CEBPB-mediated TWIST2 transcription to promote chemoresistance in LUAD

Abstract

Lung cancer remains one of the most prevalent malignancies worldwide. This study investigates the role of histone deacetylase 4 (HDAC4) in mediating chemoresistance in lung adenocarcinoma (LUAD). Super-enhancers (SEs), known to regulate aberrant gene expression, are critical drivers of tumor progression. We identified a specific super-enhancer region associated with HDAC4, referred to as HDAC4-SE. Among its nearby genes, TWIST2 emerged as a key player, strongly linked to chemoresistance and the epithelial-to-mesenchymal transition (EMT). We demonstrated that HDAC4-SE regulates TWIST2 expression, thereby contributing to chemoresistance in LUAD.

Through bioinformatics analysis, we identified transcription factors binding to both the promoter of TWIST2 and the activation region of HDAC4-SE, with CCAAT/enhancer-binding protein beta (CEBPB) identified as a central regulator. Chromatin immunoprecipitation (ChIP) assays confirmed that CEBPB binds to both the HDAC4-SE and the TWIST2 promoter. Additionally, our investigation into the involvement of long non-coding RNAs (lncRNAs) revealed that LINC01940 might mediate the regulatory effects of HDAC4-SE on downstream genes. In conclusion, we uncovered a novel HDAC4-SE/LINC01940/CEBPB/TWIST2 signaling pathway that drives chemoresistance and tumor progression in LUAD. This pathway offers promising insights into potential therapeutic targets to overcome chemoresistance in lung cancer.