SMARCB1-driven EGFR-GLI1 epigenetic alterations in lung cancer progression and therapy are differentially modulated by MEOX2 and GLI-1

Lung cancer remains the leading cause of cancer-related mortality globally, with genes such as SMARCB1, MEOX2, and GLI-1 playing significant roles in its malignancy. Despite their known involvement, the specific molecular contributions of these genes to lung cancer progression, particularly their effects on epigenetic modifications on oncogenes sequences as EGFR and GLI-1, and their influence in the response to EGFR-TKI-based therapies, have not been fully explored. Our study reveals how MEOX2 and GLI-1 are key molecular modulators of the GLI-1 and EGFR-epigenetic patterns, which in turn transcriptionally and epigenetically affect EGFR gene expression in lung cancer. Additionally, MEOX2 was found to significantly promote in vivo lung tumor progression and diminish the effectiveness of EGFR-TKI therapies. Conversely, mSWI/SNF derived subunit SMARCB1 was detected to suppress tumor growth and enhance the oncological therapeutic response in in vivo studies by inducing epigenetic modifications in the GLI-1 and EGFR genetic sequences. Furthermore, our results suggest that BRD9 may contribute to the activation of both lung cancer oncogenes GLI-1 and EGFR. Such findings suggest that SMARCB1 and MEOX2 could serve as important prognosis biomarkers and target genes in human lung cancer therapy, offering new opportunities for the development of more effective and selective treatment strategies in the field of lung malignant diseases.