Elucidating Omomyc specific action in cancer: a sensitive controller of oncogenic Myc

The involvement of Myc in a wide range of molecular functions makes it, probably, the most studied transcription factor for 30 years. Myc deregulation is common in at least 70% of human tumors and gives rise to a wide variety of oncogenic phenotypes, including breast, lung, cervical, ovarian and brain cancer. Therefore, our primary interest was to interfere with Myc function in Glioblastoma Stem Cells (GSCs) and Burkitt’s lymphoma cells, using a small peptide, named Omomyc. It is a Myc-bHLH mutant with outstanding capabilities to inhibit several types of human cancers. Omomyc displayed a significant impact on tumoral behavior in both model systems. This occurs because Omomyc replaces Myc at promoters and disrupts Myc protein network (Savino et al., 2011), affecting the expression of all those key genes - Myc target and not - directly involved in tumorigenesis. Furthermore, we found that Myc and Omomyc interact with the Protein Arginine Methyltransferase 5 (PRMT5) (Mongiardi et al. 2015), which catalyses the symmetrical di-methylation of RNA polymerase II (RNAPII) at R1810, allowing proper termination and splicing of transcripts (Zhao et al., 2016). Myc regulates many aspects of transcription by RNAPII, as activation, pause release and elongation, but its role in termination is unknown. We found that Myc overexpression strongly increases symmetrical RNAPII arginine di-methylation (R1810me2s), while the concomitant expression of Omomyc counteracts this capacity. In addition, Omomyc expression modulates the RNAPII amount at Termination Transcription sites (TTSs) versus Transcription Start Sites (TSSs) in several genes. Altogether, these findings suggest that Myc modulates transcription termination through R1810me2s-RNAPII. Therefore, Myc overexpression may deregulate this process by influencing RNAP II arginine di-methylation levels, contributing to tumorigenesis. In this regard, Omomyc may fine-tune the expression of a variety of genes altered by Myc in cancer, affecting the PRMT5/Myc/RNAPII-R1810me2s axis.