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

Abstract

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.