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Muscleblind-like 2 controls the hypoxia response of cancer cells

Fischer, Sandra and Di Liddo, Antonella and Taylor, Katarzyna and Gerhardus, Jamina S. and Sobczak, Krzysztof and Zarnack, Kathi and Weigand, Julia E. (2020):
Muscleblind-like 2 controls the hypoxia response of cancer cells.
In: RNA (New York, N.Y.), 26 (5), pp. 648-663. Cold Spring Harbor Laboratory Press / RNA Society, ISSN 1469-9001,
DOI: 10.1261/rna.073353.119,
[Article]

Abstract

Hypoxia is a hallmark of solid cancers, supporting proliferation, angiogenesis, and escape from apoptosis. There is still limited understanding of how cancer cells adapt to hypoxic conditions and survive. We analyzed transcriptome changes of human lung and breast cancer cells under chronic hypoxia. Hypoxia induced highly concordant changes in transcript abundance, but divergent splicing responses, underlining the cell type-specificity of alternative splicing programs. While RNA-binding proteins were predominantly reduced, hypoxia specifically induced muscleblind-like protein 2 (MBNL2). Strikingly, MBNL2 induction was critical for hypoxia adaptation by controlling the transcript abundance of hypoxia response genes, such as vascular endothelial growth factor A ( MBNL2 depletion reduced the proliferation and migration of cancer cells, demonstrating an important role of MBNL2 as cancer driver. Hypoxia control is specific for MBNL2 and not shared by its paralog MBNL1. Thus, our study revealed MBNL2 as central mediator of cancer cell responses to hypoxia, regulating the expression and alternative splicing of hypoxia-induced genes.

Item Type: Article
Erschienen: 2020
Creators: Fischer, Sandra and Di Liddo, Antonella and Taylor, Katarzyna and Gerhardus, Jamina S. and Sobczak, Krzysztof and Zarnack, Kathi and Weigand, Julia E.
Title: Muscleblind-like 2 controls the hypoxia response of cancer cells
Language: English
Abstract:

Hypoxia is a hallmark of solid cancers, supporting proliferation, angiogenesis, and escape from apoptosis. There is still limited understanding of how cancer cells adapt to hypoxic conditions and survive. We analyzed transcriptome changes of human lung and breast cancer cells under chronic hypoxia. Hypoxia induced highly concordant changes in transcript abundance, but divergent splicing responses, underlining the cell type-specificity of alternative splicing programs. While RNA-binding proteins were predominantly reduced, hypoxia specifically induced muscleblind-like protein 2 (MBNL2). Strikingly, MBNL2 induction was critical for hypoxia adaptation by controlling the transcript abundance of hypoxia response genes, such as vascular endothelial growth factor A ( MBNL2 depletion reduced the proliferation and migration of cancer cells, demonstrating an important role of MBNL2 as cancer driver. Hypoxia control is specific for MBNL2 and not shared by its paralog MBNL1. Thus, our study revealed MBNL2 as central mediator of cancer cell responses to hypoxia, regulating the expression and alternative splicing of hypoxia-induced genes.

Journal or Publication Title: RNA (New York, N.Y.)
Journal volume: 26
Number: 5
Publisher: Cold Spring Harbor Laboratory Press / RNA Society
Divisions: 10 Department of Biology
10 Department of Biology > RNA Biochemistry
Date Deposited: 05 Mar 2021 08:14
DOI: 10.1261/rna.073353.119
Identification Number: pmid:32127384
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