NFYA alternative cleavage and polyadenylation in cancer

The majority of human genes undergo alternative cleavage and polyadenylation (APA) regulating 3’UTR length and accessibility, thus affecting mRNA stability and protein level by altering microRNA and RNA-binding protein (RBP) activity. NFYA is an oncogene encoding for the regulatory subunit of the nuclear transcription factor Y, which controls key transcriptional changes in pathways broadly deregulated in cancer. NFYA is strongly overexpressed in human tumors and the poor correlation between NF-YA protein and mRNA in different cancer types suggests that APA may be as relevant as other mechanisms to control NF-YA activity in cancer. Concerning this, our bioinformatic analyses identified multiple APA sites resulting in four possible NFYA 3’UTRs, not yet correctly annotated. We observed that tumor and immortalized cells mainly use shorter 3’UTRs compared with normal cells, which prevalently use longer ones. In this regard, we found an increased NF-YA protein/mRNA ratio to be associated with higher usage of shorter 3’UTRs. Moreover, the effect of different NFYA 3’UTRs on transcript stability, protein level, and microRNA and RBP binding is under study employing different strategies to alter NFYA 3’UTR usage. We found that increased usage of shorter NFYA 3’UTRs, induced either exogenously or endogenously, is associated with higher NF-YA protein/mRNA ratio in prostate adenocarcinoma cells. Thus, NFYA APA can be a post-transcriptional mechanism important to control NF-YA activity in cancer. Notably, the emerging application of ASOs in the clinics opens the possibility to target/mask polyadenylation signals, microRNA or RBP binding sites to therapeutically manipulate the effects of APA in cancer. Overall, our studies intend to characterize NFYA APA in the cancer context from a functional and biological point of view.