Identification of anti-tumoral feedback loop between VHLα and hnRNPA2B1 in renal cancer

Our previous study identified a novel VHLα isoform which negatively modulated hnRNPA2B1 expression and therefore influenced pyruvate kinase transcript splicing in renal cancer, while the regulation and initiation of alternative translation are largely unknown. Here we unraveled the CUG-mediated translation start of VHLα, which was subjected to the regulation by both eukaryotic initiator factor eIF2A and RNA helicase eIF4A. Unexpectedly, we found hnRNPA2B1 promoted VHLα alternative translation as well via direct interaction with its octadic pentamer region of VHL transcript. The N-terminal of VHLα was indispensable in mediating ubiquitination of hnRNPA2B1 at lysine residues 274 and 305. We further identified aberrant overexpression of c-myc as upstream oncogenic signaling to positively regulate hnRNPA2B1 transcription in renal cancer. Therefore, our data suggested an anti-tumoral feedback loop between VHLα and hnRNPA2B1.