MYC and DNMT 3A‐mediated DNA methylation represses micro RNA ‐200b in triple negative breast cancer

Triple‐negative breast cancer ( TNBC ) is the most aggressive breast cancer subtype with a poor prognosis. The micro RNA ‐200 (miR‐200) family has been associated with breast cancer metastasis. However, the epigenetic mechanisms underlying miR‐200b repression in TNBC are not fully elucidated. In thi...

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Published in:Journal of cellular and molecular medicine 2018-12, Vol.22 (12), p.6262-6274
Main Authors: Pang, Yamei, Liu, Jian, Li, Xiang, Xiao, Guodong, Wang, Huangzhen, Yang, Ganghua, Li, Yanbo, Tang, Shou‐Ching, Qin, Sida, Du, Ning, Zhang, Henggang, Liu, Dapeng, Sun, Xin, Ren, Hong
Format: Article
Language:English
Subjects:
Breast cancer
CpG islands
DNA methylation
DNA methyltransferase
Feedback loops
Helix-loop-helix proteins (basic)
Homeobox
Mesenchyme
Metastases
MicroRNAs
miRNA
Myc protein
Zinc
Zinc finger proteins
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Summary:Triple‐negative breast cancer ( TNBC ) is the most aggressive breast cancer subtype with a poor prognosis. The micro RNA ‐200 (miR‐200) family has been associated with breast cancer metastasis. However, the epigenetic mechanisms underlying miR‐200b repression in TNBC are not fully elucidated. In this study, we found that MYC proto‐oncogene, bHLH transcription factor (MYC) and DNA methyltransferase 3A ( DNMT 3A) were highly expressed in TNBC tissues compared with other breast cancer subtypes, while miR‐200b expression was inhibited significantly. We demonstrated that MYC physically interacted with DNMT 3A in MDA ‐ MB ‐231 cells. Furthermore, we demonstrated that MYC recruited DNMT 3A to the miR‐200b promoter, resulting in proximal CpG island hypermethylation and subsequent miR‐200b repression. MiR‐200b directly inhibited DNMT 3A expression and formed a feedback loop in TNBC cells. MiR‐200b overexpression synergistically repressed target genes including zinc‐finger E‐box‐binding homeobox factor 1, Sex determining region Y‐box 2 (SOX2), and CD 133, and inhibited the migration, invasion and mammosphere formation of TNBC cells. Our findings reveal that MYC can collaborate with DNMT 3A on inducing promoter methylation and miR‐200b silencing, and thereby promotes the epithelial to mesenchymal transition and mammosphere formation of TNBC cells.
ISSN:1582-1838
1582-4934
DOI:10.1111/jcmm.13916