Identification of Epigenetic Biomarkers of Lung Adenocarcinoma through Multi-Omics Data Analysis

Abstract

Epigenetic mechanisms such as DNA methylation or histone modifications are essential for the regulation of gene expression and development of tissues. Alteration of epigenetic modifications can be used as an epigenetic biomarker for diagnosis and as promising targets for epigenetic therapy. A recent study explored cancer-cell specific epigenetic biomarkers by examining different types of epigenetic modifications simultaneously. However, it was based on microarrays and reported biomarkers that were also present in normal cells at a low frequency. Here, we first analyzed multi-omics data (including ChIP-Seq data of six types of histone modifications: H3K27ac, H3K4me1, H3K9me3, H3K36me3, H3K27me3, and H3K4me3) obtained from 26 lung adenocarcinoma cell lines and a normal cell line. We identified six genes with both H3K27ac and H3K4me3 histone modifications in their promoter regions, which were not present in the normal cell line, but present in ≥85% (22 out of 26) and ≤96% (25 out of 26) of the lung adenocarcinoma cell lines. Of these genes, NUP210 (encoding a main component of the nuclear pore complex) was the only gene in which the two modifications were not detected in another normal cell line. RNA-Seq analysis revealed that NUP210 was aberrantly overexpressed among the 26 lung adenocarcinoma cell lines, although the frequency of NUP210 overexpression was lower (19.3%) in 57 lung adenocarcinoma tissue samples studied and stored in another database. This study provides a basis to discover epigenetic biomarkers highly specific to a certain cancer, based on multi-omics data at the cell population level.

Histone methyltransferase SETD1A participates in lung cancer progression

“…Enhanced H3K4me3 was con rmed in lung cancer 12,13 , which was attributed to upregulated SETD1A, owing to no differences in other histone methylases between lung cancer tissues and adjacent nontumor tissues (FIGURE S5). However, the downstream effects of SETD1A are different in different tumors.…”

“…SETD1A is an important methyltransferase to catalyze H3K4me3. Because more H3K4me3 was present in lung cancer cell lines 12,13 , we monitored the level of H3K4me3 in SETD1A knockdown A549 cells. Immuno uorescence showed that SETD1A silencing resulted in an obvious signal reduction of H3K4me3 in the global nucleus (FIGURE 5A-B).…”

“…Data of cumulative overall survival of patients with lung carcinoma is from TCGA database. SETD1A expression in different cell line is from previous report 12 . Enhanced H3K4me3 signaling in cell line of lung cancer was con rmed with ENCODE (https://www.encodeproject.org/), the database collects and veri es CHIP-seq results.…”

“…Interestingly, other research also indicated that an increased H4K4me3 level was present in lung adenocarcinoma cell lines and participated in abnormal transcriptional regulation. However, the mechanism is not clear 12,13 .…”

Epigenetics in non-small cell lung carcinomas

“…51 This findings suggest the importance of the three main epigenetic mechanisms, DNA methylation, histone code modifications and chromatin remodeling complexes in cancer progression (table I and II). [52][53][54][55][56][57][58] Along with, overexpression of BRG1 and BRM in the cisplatin toxicity, 50 or doxorubicin chemo resistance mechanisms associated with the expression of the subunits SMARCB1 and SMARCA4 (BRG1) in front to NSCLC cells. 51 All of that, suggesting the importance of the three main epigenetic mechanisms DNA methylation, histone code modifications and chromatin remodeling complexes in cancer progression and potential new oncological therapeutic strategies in NSCLC, all of which have been shown in…”