Identification of a Novel Myc Associated Oncogenic Enhancer RNA

Amplification or elevated expression of the Myc oncogene is a major mechanism associated with malignant tumor progression and poor prognosis in many cancers, including breast cancer. Enhancers play dominant roles in driving the overexpression of oncogenes. Long noncoding RNA known as enhancer RNA (eRNA) produced from enhancers can mediate the function of enhancers. Although many eRNA-dependent regulatory functions have been demonstrated, direct association of eRNA, with its immediate effectors and regulators, has not been explored and little is known about how eRNA might work directly to affect gene expression. In our efforts to discover potential oncogenic eRNAs, we identified a novel eRNA that drives Myc expression in breast cancer cells that we named MYC EN-1. We find that MYC EN-1 is stabilized selectively in cancer cells via possible circularization and that reduction of MYC EN-1 decreases Myc transcription, protein expression, and cell viability. The transcriptome profile after knocking down of MYC EN-1 and Myc mRNA, respectively, reveals that both eRNA and mRNA share a large portion of similar transcriptomic changes. Biochemical characterization of MYC-EN-1 reveals that it is intimately associated with both Myc pre-mRNA and mature mRNA as it is synthesized and processed from its genomic locus. This physical interaction between MYC-EN-1 and Myc mRNA is achieved through direct interaction by direct base pairing. Our study has uncovered a broad role of oncogenic eRNAs with ability to promote target mRNA transcription.