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.