Assessing MYC-driven co- and post-transcriptional alterations in prostate cancer with direct RNA long-read sequencing

MYC is a master transcription factor and oncoprotein and its deregulation is a major driver of prostate cancer (PC) tumorigenesis and progression. Despite advances in the treatment of early disease, there are few therapeutic options for the aggressive PC phenotype. Aberrant alternative splicing and post-transcriptional alterations in RNA methylation can contribute to the heterogeneous phenotypes of PC. In this light, we assessed MYC-driven co- and post-transcriptional alterations in PC using long-read direct RNA sequencing data. By a de novo isoform reconstruction we identified 19,543 isoforms, shedding light on 5,218 unprecedented annotated mRNA isoforms. Differential expression at gene- and isoform-level suggested the potential contribution of MYC in regulating expression levels of factors acting in the spliceosome machinery and post-transcriptional processes such as RNA methylation and RNA localization. Moreover, we characterized MYC-driven alternative splicing events in genes implicated in spliceosome activity. By mapping m6A methylation sites along the full-length isoforms, we identified isoforms that are differentially methylated by MYC, including those encoding SF3B1. Together, our findings shed light on regulators of the multifaceted landscape of MYC-driven co- and post-transcriptional alterations in PC, which could be novel candidates for therapeutic purposes for MYC-driven cancers such as PC