DNA hypomethylation drives changes in MAGE-A gene expression resulting in alteration of proliferative status of cells
DNA hypomethylation drives changes in MAGE-A gene expression resulting in alteration of proliferative status of cells
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DOI：
10.1186/s41021-020-00162-2
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发表时间：
2020-07-30
影响因子：
1.7
通讯作者：
Ramanathan, Saumya
中科院分区：
文献类型：
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作者：
Colemon, Ashley;Harris, Taylor M.;Ramanathan, Saumya
黑色素瘤抗原基因（MAGE）是一个基因家族，因其独特的表达模式而引起了科学家的兴趣。MAGE的一个子集（I型）在精原细胞中表达，而在其他体细胞组织中不表达，然后在许多癌症中重新表达。由于这种表达模式，I型MAGE通常被称为癌症-睾丸抗原，而II型MAGE在表达中更普遍存在。本研究确定了肿瘤-睾丸抗原的MAGE-A亚家族异常表达的原因和后果。我们已经发现MAGE-A基因受DNA甲基化的调控，这一点在用DNA甲基转移酶抑制剂5-氮杂胞苷处理后得到证实。此外，对现有甲基化组测序数据的生物信息学分析也证实了我们的发现。表达某些MAGE-A基因的结果是增加细胞增殖和集落形成，以及对化疗剂5-氟尿嘧啶和DNA损伤剂亚砷酸钠的抗性。总之，这些数据表明，DNA甲基化在调节MAGE-A基因的表达中起着至关重要的作用，MAGE-A基因随后充当细胞增殖、锚定非依赖性生长和化学抗性的驱动因素，这对癌细胞存活至关重要。
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 theMAGE-Asubfamily of cancer-testis antigens. We have discovered thatMAGE-Agenes 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 certainMAGE-Agenes 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 ofMAGE-Agenes which then act as drivers of cell proliferation, anchorage-independent growth and chemo-resistance that is critical for cancer-cell survival.