Methylation of the RELA Gene is Associated with Expression of NF-κB1 in Response to TNF-α in Breast Cancer

Abstract

The nuclear factor (NF)-κB family of transcriptional factors plays a critical role in inflammation, immunoregulation, cell differentiation, and tumorigenesis. This study aims to investigate the role of methylation of genes encoding for the NF-κB family in breast cancer. We analyze the DNA methylation status of the NFKB1 gene and the RELA gene in breast cancer using pyrosequencing. The expression of NF-κB1 and RELA proteins is assessed and the level of RNA transcripts in frozen tissue is determined using RT-PCR. There is no statistically significant difference in the methylation status of the NFKB1 and the RELA genes between tumors and normal tissues. The methylation status of the NFKB1 gene and the RELA gene is not significantly associated with the levels of NF-κB1 transcripts in tumor tissues. However, the methylation level of the RELA gene is significantly associated with the level of tumor necrosis factor (TNF)-α. In addition, the level of NF-κB1 transcripts was associated with the levels of TNF-α and IL-4. In tumors with positive TNF-α, the increased methylation level of the RELA gene is significantly associated with the positive expression of NF-κB1 transcripts. These results demonstrate that the level of the RELA gene methylation is related to the levels of NF-κB1 transcripts under the influence of TNF-α. Further study is needed to determine how TNF-α is involved in the methylation of the RELA gene and the subsequent expression of NF-κB1.

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“…Additionally, MAPK1 affects the progression of breast and ovarian cancers by participating in multiple signalling pathways [ 45 , 46 ], and AKT1 is closely related to cancer and a variety of diseases through its roles in metabolic regulation and signalling pathways [ 47 , 48 ]. RELA is an important target gene in NF- κ B signalling; Lu and Yarbrough [ 49 ] reported that RELA dephosphorylation inhibits tumour development [ 49 ], and other studies have indicated that RELA methylation and subsequent activation of multiple downstream genes contribute to the regulation of breast cancer progression [ 50 , 51 ]. JUN is an activator protein-1 transcription factor subunit that regulates the expression of multiple genes critical to cell proliferation, differentiation, and apoptosis [ 52 ].…”

In silico approach to understand epigenetics of POTEE in ovarian cancer

“…Group A associators overpowered the epigenetic link to group B interactors. RELA has shown an increased methylation level that is significant in the progression of breast cancer [ 47 ], HMOX2 has shown an increased hypomethylation in endometriosis [ 48 ], while EZH2 mediates histone modification H3K27m3 and causes several cancers [ 49 ]. ERRFI1 is discerned to have an epigenetic downregulation in neuroblastoma tumors [ 50 ], and WDR1 has been shown to get overexpressed in non-small cell lung cancer (NSCLC) [ 51 ], whereas, p10Y-ERBB3-1 is discerned to have shown histone methylation of H3K27m3 in general [ 52 ].…”

“…This evidence suggests that since the majority of the network associators of POTEE are epigenetically activated in many cancers, it is quite natural for POTEE paralog to get over-expressed and epigenetically regulated in ovarian cancer too. Moreover, there exist various experimental studies [ 19 , 20 , 44 ], [ 45 ], [ 46 ], [ 47 ], [ 48 ], [ 49 ], [ 50 ], [ 51 ], [ 52 ], [ 53 ], [ 54 ] that discern its epigenetic dynamics in different diseases.…”

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“…NF-κB consists of NFKB1 or NFKB2 combined with REL, RELA or RELB. NFKB1 compounded with the gene product RELA is the most extensive form [ 44 , 45 ]. For rheumatoid arthritis, Sabir's study used a weighted gene co-expression network to analyze the function of the NF-κB protein family and its regulators, and proved that these genes (such as NFKB2) may be involved in the inflammation and immune pathogenesis of rheumatoid arthritis with an important role [ 46 ].…”