Super-enhancer MYCNOS-SE promotes chemoresistance in small cell lung cancer by recruiting transcription factors CTCF and KLF15.

Abstract

Small cell lung cancer (SCLC) is an aggressive form of lung cancer that often becomes resistant to chemotherapy. Understanding the molecular mechanisms of chemoresistance is crucial for identifying effective therapeutic targets. In this study, we used RNA-Seq to identify highly expressed molecules associated with chemoresistance. We also performed H3K27Ac and ATAC-Seq binding analyses to identify super-enhancers (SE) and their corresponding transcription factors. Both in vitro and in vivo experiments were conducted to examine the impact of these molecules and clinical samples were collected to establish their prognostic value. Our findings revealed elevated expression of MYCNOS, which exhibited chemoresistant properties in both in vitro and in vivo models of SCLC. We identified MYCNOS-SE as a significant SE in SCLC that regulates the distal target gene MYCNOS. This SE recruits transcription factors CTCF and KLF15 to regulate MYCNOS expression. Additionally, MYCNOS, an antisense of MYCN, was found to modulate chemotherapy sensitivity through the NOTCH pathway. This study highlights the significance of SE -regulated target genes as markers for chemoresistance in SCLC. Furthermore, it suggests that MYCNOS could serve as a predictor to identify patients who may benefit from NOTCH inhibitors. These findings provide valuable insights for future studies aimed at developing therapeutic strategies targeting these identified pathways.