Identification of HIF-dependent alternative splicing in gastrointestinal cancers and characterization of a long, coding isoform of SLC35A3.

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 many 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 gastrointestinal 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. Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Citation

Philipp Markolin, Natalie Davidson, Christian K Hirt, Christophe D Chabbert, Nicola Zamboni, Gerald Schwank, Wilhelm Krek, Gunnar Rätsch. Identification of HIF-dependent alternative splicing in gastrointestinal cancers and characterization of a long, coding isoform of SLC35A3. Genomics. 2021 Mar;113(2):515-529

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PMID: 33418078

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