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SF3B1 promotes tumor malignancy through splicing-independent co-activation of HIF1α


Abstract

Heterozygous mutations in the splicing factor SF3B1 are frequently occurring in various cancers and drive tumor progression through the activation of cryptic splice sites in multiple genes. Recent studies moreover demonstrate a positive correlation between expression levels of wildtype SF3B1 and tumor malignancy, although the underlying mechanisms for this phenomenon remain elusive. Here, we report that SF3B1 acts as a coactivator for hypoxia-inducible factor (HIF)1α through a splicing-independent mechanism. By directly interacting with HIF1α, SF3B1 augments HIF1α-HIF1β heterodimer binding to hypoxia response elements, and facilitates full transcriptional response of HIF target genes. We further validate the relevance of this mechanism for tumor progression, and show that monoallelic deletion of <jats:italic>Sf3b1</jats:italic> impedes pancreatic cancer formation via HIF signaling. Altogether our work demonstrates a pivotal role of SF3B1 in the adaptation to hypoxia, suggesting a causal link between high SF3B1 levels and cancer aggressiveness.

Abstract

Heterozygous mutations in the splicing factor SF3B1 are frequently occurring in various cancers and drive tumor progression through the activation of cryptic splice sites in multiple genes. Recent studies moreover demonstrate a positive correlation between expression levels of wildtype SF3B1 and tumor malignancy, although the underlying mechanisms for this phenomenon remain elusive. Here, we report that SF3B1 acts as a coactivator for hypoxia-inducible factor (HIF)1α through a splicing-independent mechanism. By directly interacting with HIF1α, SF3B1 augments HIF1α-HIF1β heterodimer binding to hypoxia response elements, and facilitates full transcriptional response of HIF target genes. We further validate the relevance of this mechanism for tumor progression, and show that monoallelic deletion of <jats:italic>Sf3b1</jats:italic> impedes pancreatic cancer formation via HIF signaling. Altogether our work demonstrates a pivotal role of SF3B1 in the adaptation to hypoxia, suggesting a causal link between high SF3B1 levels and cancer aggressiveness.

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Item Type:Working Paper
Communities & Collections:04 Faculty of Medicine > Institute of Pharmacology and Toxicology
07 Faculty of Science > Institute of Pharmacology and Toxicology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2020
Deposited On:19 Jan 2021 16:37
Last Modified:19 Jan 2021 16:37
Series Name:arXiv.org
ISSN:2331-8422
OA Status:Green
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1101/2020.11.10.376780

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