The importance of enhancer methylation for epigenetic regulation of tumorigenesis in squamous lung cancer

Lung squamous cell carcinoma (LUSC) is a subtype of non-small cell lung cancer (NSCLC). LUSC occurs at the bronchi, shows a squamous appearance, and often occurs in smokers. To determine the epigenetic regulatory mechanisms of tumorigenesis, we performed a genome-wide analysis of DNA methylation in tumor and adjacent normal tissues from LUSC patients. With the Infinium Methylation EPIC Array, > 850,000 CpG sites, including ~350,000 CpG sites for enhancer regions, were profiled, and the differentially methylated regions (DMRs) overlapping promoters (pDMRs) and enhancers (eDMRs) between tumor and normal tissues were identified. Dimension reduction based on DMR profiles revealed that eDMRs alone and not pDMRs alone can differentiate tumors from normal tissues with the equivalent performance of total DMRs. We observed a stronger negative correlation of LUSC-specific gene expression with methylation for enhancers than promoters. Target genes of eDMRs rather than pDMRs were found to be enriched for tumor-associated genes and pathways. Furthermore, DMR methylation associated with immune infiltration was more frequently observed among enhancers than promoters. Our results suggest that methylation of enhancer regions rather than promoters play more important roles in epigenetic regulation of tumorigenesis and immune infiltration in LUSC. Lung cancer: importance of enhancer methylation in tumor development The aberrant methylation of specific regions of DNA may play a significant role in regulating tumorigenesis in lung squamous cell carcinoma (LUSC). LUSC development is linked to smoking, but epigenetic regulation mechanisms in LUSC are unclear. Hye Ryun Kim at Yonsei University College of Medicine and Insusk Lee at Yonsei University in Seoul, Korea, and co-workers compared DNA methylation patterns in samples of tumor and adjacent normal tissues from 37 LUSC patients. They paid particular attention to differentially methylated regions (DMRs) that overlapped short DNA sequences that regulate gene expression. DMRs overlapping enhancers—regions that regulate expression of a gene from a distance—rather than promoters were more associated with tumor formation from normal tissues, suggesting that methylation of enhancers rather than promoters could be a more important player in cancer development.