HPV shapes tumor transcriptome by globally modifying the pool of RNA binding protein-binding motif

Human papillomavirus (HPV) positive head and neck cancer displayed specific transcription landscape but the underlying molecular mechanisms are not fully determined. Here, we interestingly found that HPV infection could globally elongate the 3’-untranslated regions (3’UTRs) in the majority of alternative polyadenylation (APA)-containing genes. Counterintuitively, the 3’UTR elongation does not affect their resident gene expression. Rather, they significantly increase the number of binding sites for RNA-binding proteins (RBPs) and subsequently upregulate a group of oncogenic genes by absorbing RBPs. A significant fraction of HPV affected genes are regulated through such mechanism that is 3’UTR-mediated recruitment of RBPs. As an example, we observed that HPV infection increases the length of 3’UTR of RBM25 transcript and hence recruits much more RNA binding protein including FUS and DGCR8. Consequently, in the absence of FUS and DGCR8 regulation, PD-1 was rescued and up-regulated after HPV infection. Taken together, our findings not only suggest a novel paradigm of how oncogenic viruses shape tumor transcriptome by modifying the 3’UTR, but also present a previously unrecognized layer of APA—RBP interplay in this molecular hierarchy. Modification of the pool of RBP-binding motif might expand our understandings into virus-associated carcinogenesis.