MYC and DNMT3A‐mediated DNA methylation represses microRNA‐200b in triple negative breast cancer

Triple‐negative breast cancer (TNBC) is the most aggressive breast cancer subtype with a poor prognosis. The microRNA‐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 (DNMT3A) 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 DNMT3A in MDA‐MB‐231 cells. Furthermore, we demonstrated that MYC recruited DNMT3A to the miR‐200b promoter, resulting in proximal CpG island hypermethylation and subsequent miR‐200b repression. MiR‐200b directly inhibited DNMT3A 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 CD133, and inhibited the migration, invasion and mammosphere formation of TNBC cells. Our findings reveal that MYC can collaborate with DNMT3A on inducing promoter methylation and miR‐200b silencing, and thereby promotes the epithelial to mesenchymal transition and mammosphere formation of TNBC cells.