DNA hypomethylation drives changes in MAGE-A gene expression resulting in alteration of proliferative status of cells

Abstract

Melanoma Antigen Genes (MAGEs) are a family of genes that have piqued the interest of scientists for their unique expression pattern. A subset of MAGEs (Type I) are expressed in spermatogonial cells and in no other somatic tissue, and then re-expressed in many cancers. Type I MAGEs are often referred to as cancer-testis antigens due to this expression pattern, while Type II MAGEs are more ubiquitous in expression. This study determines the cause and consequence of the aberrant expression of the MAGE-A subfamily of cancer-testis antigens. We have discovered that MAGE-A genes are regulated by DNA methylation, as revealed by treatment with 5-azacytidine, an inhibitor of DNA methyltransferases. Furthermore, bioinformatics analysis of existing methylome sequencing data also corroborates our findings. The consequence of expressing certain MAGE-A genes is an increase in cell proliferation and colony formation and resistance to chemo-therapeutic agent 5-fluorouracil and DNA damaging agent sodium arsenite. Taken together, these data indicate that DNA methylation plays a crucial role in regulating the expression of MAGE-A genes which then act as drivers of cell proliferation, anchorage-independent growth and chemo-resistance that is critical for cancer-cell survival.

Transcription Silencing and CpGs Hypermethylation as Therapeutic Gene Editing in Clinical Colorectal Adenocarcinoma Repression

“…Therefore, remodeling and silencing of this intracellular molecular system in cancer cells represents a therapeutic strategy in cancer therapy. 24 In addition, DNA damage, increasing chromatin de-condensation, and chromosomal instability are all related to cancer progression. Long-and short-interspersed nuclear components, as well as classical satellites, are highly methylated.…”

Mutational signatures and their association with survival and gene expression in urological carcinomas

“…The possible biological relationship between APOBEC enzymes and MAGE family members or kallikreins remains unstudied. However, it is known that the expression of MAGE-A genes is regulated by DNA methylation [55] , which could be modified by APOBEC enzymes.…”

DNA Methylation in Solid Tumors: Functions and Methods of Detection

“…For instance, genes from MAGEA gene cluster (melanoma-associated antigen A) are expressed only in spermatogonial cells and not in other somatic tissues. However, they can be again re-expressed in various cancers due to demethylation of their promoters [ 24 ]. Accordingly, abnormal expression of MAGEA genes is associated with increased aggressiveness and malignancy of breast, lung, and colorectal tumors [ 25 ].…”