A novel mechanism by which c-MYC is aberrantly activated by epigenetic silencing in cancer cells

Proto-oncogenes are abnormally activated in nearly all types of tumors. However, the epigenetic mechanism of proto-oncogene activation has not yet been well elucidated. Here, we show that a subset of proto-oncogenes, including c - MYC , possess antisense RNAs. Upregulation of c - MYC in cancer tissues was attributed to the silencing of its antisense RNA MYC-AS1 via DNA hypermethylation. MYC-AS1 RNA markedly inhibited the proliferation of cancer cells in vitro and impeded tumor growth in nude mice in vivo by repressing the expression of c - MYC via an RNAi mechanism. MYC-AS1 RNA bound directly to the HuR protein in the cytoplasm, enhancing the RNA stability of MYC-AS1. Furthermore, MYC-AS1 inhibited c -MYC-targeted gene LDHA expression. Our work provides a novel mechanism by which c - MYC is activated in cancer cells by epigenetic silencing of its antisense RNA, which functions as a tumor suppressor.