PT - JOURNAL ARTICLE AU - Markolin, Philipp AU - Davidson, Natalie AU - Hirt, Christian K. AU - Chabbert, Christophe D. AU - Zamboni, Nicola AU - Schwank, Gerald AU - Krek, Wilhelm AU - Rätsch, Gunnar TI - Characterisation of HIF-dependent alternative isoforms in pancreatic cancer AID - 10.1101/826156 DP - 2019 Jan 01 TA - bioRxiv PG - 826156 4099 - http://biorxiv.org/content/early/2019/10/31/826156.short 4100 - http://biorxiv.org/content/early/2019/10/31/826156.full AB - Intra-tumor hypoxia is a common feature in many solid cancers. Although transcriptional targets of hypoxia-inducible factors (HIFs) have been well characterized, alternative splicing or processing of pre-mRNA transcripts which occurs during hypoxia and subsequent HIF stabilization is much less understood. Here, we identify HIF-dependent alternative splicing events after whole transcriptome sequencing in pancreatic cancer cells exposed to hypoxia with and without downregulation of the aryl hydrocarbon receptor nuclear translocator (ARNT), a protein required for HIFs to form a transcriptionally active dimer. We correlate the discovered hypoxia-driven events with available sequencing data from pan-cancer TCGA patient cohorts to select a narrow set of putative biologically relevant splice events for experimental validation. We validate a small set of candidate HIF-dependent alternative splicing events in multiple human cancer cell lines as well as patient-derived human pancreatic cancer organoids. Lastly, we report the discovery of a HIF-dependent mechanism to produce a hypoxia-dependent, long and coding isoform of the UDP-N-acetylglucosamine transporter SLC35A3.