Abstract
BackgroundChemoresistance is a primary clinical challenge for the management of small cell lung cancer. Additionally, transcriptional regulation by super enhancer (SE) has an important role in tumor evolution. The functions of SEs, a key class of noncoding DNA cis-regulatory elements, have been the subject of many recent studies in the field of cancer research.MethodsIn this study, using chromatin immunoprecipitation-sequencing and RNA-sequencing (RNA-seq), we aimed to identify SEs associated with chemoresistance from H69AR cells. Through integrated bioinformatics analysis of the MEME chip, we predicted the master transcriptional factors (TFs) binding to SE sites and verified the relationships between TFs of SEs and drug resistance by RNA interference, cell counting kit 8 assays, quantitative real-time reverse transcription polymerase chain reaction.ResultsIn total, 108 SEs were screened from H69AR cells. When combining this analysis with RNA-seq data, 45 SEs were suggested to be closely related to drug resistance. Then, 12 master TFs were predicted to localize to regions of those SEs. Subsequently, we selected forkhead box P1 (FOXP1), interferon regulatory factor 1 (IRF1), and specificity protein 1 (SP1) to authenticate the functional relationships of master TFs with chemoresistance via SEs.ConclusionsWe screened out SEs involved with drug resistance and evaluated the functions of FOXP1, IRF1, and SP1 in chemoresistance. Our findings established a large group of SEs associated with drug resistance in small cell lung cancer, revealed the drug resistance mechanisms of SEs, and provided insights into the clinical applications of SEs.
Highlights
Chemoresistance is a primary clinical challenge for the management of small cell lung cancer
These results demonstrated that chemoresistance formation was accompanied by changes in cellular components and biological processes, such as metabolism remodeling [12]
In pathways enriched in biological processes, we chose to focus on cholesterol metabolism-related processes in addition to some lung development processes (Fig. 1f) because the results suggested that cholesterol metabolism may contribute to chemoresistance formation
Summary
Chemoresistance is a primary clinical challenge for the management of small cell lung cancer. Small cell lung cancer (SCLC) is an aggressive type of malignant tumor that shows rapid recurrence after chemotherapy and accounts for approximately 15% of all lung cancers. SCLC is the most destructive subtype of lung cancer and often exhibits neuroendocrine features [1]. SCLC is initially sensitive to chemotherapeutic drugs, rapid development of drug-resistant disease. Gene amplifications, confer SCLC with the ability to acquire chemoresistance quickly. The underlying mechanisms of specific resistances remain unknown. The extent to which rapid acquisition of drug resistance after initial treatment is dependent on gene amplification in SCLC is not yet known. Gene amplification is usually modulated by the
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