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

Autor: Markolin P; Institute of Molecular Health Sciences, ETH Zurich, 8093 Zurich, Switzerland; Biomedical Informatics Group, ETH Zurich, 8092 Zürich, Switzerland., Davidson N; Biomedical Informatics Group, ETH Zurich, 8092 Zürich, Switzerland., Hirt CK; Institute of Molecular Health Sciences, ETH Zurich, 8093 Zurich, Switzerland., Chabbert CD; Institute of Molecular Health Sciences, ETH Zurich, 8093 Zurich, Switzerland., Zamboni N; Institute of Molecular Systems Biology, ETH Zurich, 8093 Zürich, Switzerland., Schwank G; Institute of Molecular Health Sciences, ETH Zurich, 8093 Zurich, Switzerland; Biomedical Informatics Group, ETH Zurich, 8092 Zürich, Switzerland., Krek W; Institute of Molecular Health Sciences, ETH Zurich, 8093 Zurich, Switzerland., Rätsch G; Biomedical Informatics Group, ETH Zurich, 8092 Zürich, Switzerland. Electronic address: raetsch@inf.ethz.ch.
Jazyk: angličtina
Zdroj: Genomics [Genomics] 2021 Mar; Vol. 113 (2), pp. 515-529. Date of Electronic Publication: 2021 Jan 05.
DOI: 10.1016/j.ygeno.2020.12.039
Abstrakt: 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.)
Databáze: MEDLINE
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