RNA decay defines the therapeutic response to transcriptional perturbation in cancer

Transcriptionally dysregulated cancers are sensitive to the inhibition of RNA Polymerase II (RNAPII) - driven gene expression. The therapeutic effect is attributed to selective inhibition of discrete oncogenes regulated at the chromatin level, however the role of RNA stability remains largely unexplored. Using integrated transcriptomic technologies, we discovered that RNA decay is a key determinant in defining gene expression responses to transcriptional perturbation, where total RNA signatures are dominated with genes that have short transcript half-lives, including oncogenic drivers such as c-MYC. Experimentally increasing c-MYC RNA stability maintained total c-MYC RNA levels following RNAPII perturbation, despite a concordant decrease in nascent RNA. Taken together, these data demonstrate that RNA decay shapes the molecular and therapeutic response to transcriptional perturbation in cancer. HIGHLIGHTS Selective inhibition of oncogenic transcription in response to epigenetic and transcriptional inhibitors in cancer under-estimates the role of RNA decay Gene intrinsic RNA decay rates are a key determinant in shaping the total mRNA response to transcriptional perturbation in cancer Selective disruption of core-transcription factor networks is a result of short transcript half-lives Modulation of c-MYC decay rates can render it insensitive to transcriptional targeting