Bridge, Katherine orcid.org/0000-0003-1516-1459, Foxler, Daniel E, Foster, John G et al. (24 more authors) (2018) A HIF–LIMD1 negative feedback mechanism mitigates the pro‐tumorigenic effects of hypoxia. EMBO Molecular Medicine. e8304. ISSN 1757-4684
Abstract
The adaptive cellular response to low oxygen tensions is mediated by the hypoxia-inducible factors (HIFs), a family of heterodimeric transcription factors composed of HIF-α and HIF-β subunits. Prolonged HIF expression is a key contributor to cellular transformation, tumorigenesis and metastasis. As such, HIF degradation under hypoxic conditions is an essential homeostatic and tumour-suppressive mechanism. LIMD1 complexes with PHD2 and VHL in physiological oxygen levels (normoxia) to facilitate proteasomal degradation of the HIF-α subunit. Here, we identify LIMD1 as a HIF-1 target gene, which mediates a previously uncharacterised, negative regulatory feedback mechanism for hypoxic HIF-α degradation by modulating PHD2-LIMD1-VHL complex formation. Hypoxic induction of LIMD1 expression results in increased HIF-α protein degradation, inhibiting HIF-1 target gene expression, tumour growth and vascularisation. Furthermore, we report that copy number variation at the LIMD1 locus occurs in 47.1% of lung adenocarcinoma patients, correlates with enhanced expression of a HIF target gene signature and is a negative prognostic indicator. Taken together, our data open a new field of research into the aetiology, diagnosis and prognosis of LIMD1-negative lung cancers.
Metadata
Item Type: | Article | ||||||
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2018, The Author(s). | ||||||
Keywords: | Adenocarcinoma/diagnosis, Adult, Aged, Aged, 80 and over, Animals, Carcinogenesis/genetics, Cell Hypoxia/genetics, Cell Line, Tumor, Feedback, Physiological, Female, Gene Expression Regulation, Neoplastic, Humans, Hypoxia-Inducible Factor 1, alpha Subunit/genetics, Intracellular Signaling Peptides and Proteins/genetics, LIM Domain Proteins/genetics, Lung Neoplasms/diagnosis, Male, Mice, Middle Aged, Prognosis, Survival Analysis, Vascular Endothelial Growth Factor A/genetics | ||||||
Dates: |
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Institution: | The University of York | ||||||
Academic Units: | The University of York > Faculty of Social Sciences (York) > Social Policy and Social Work (York) The University of York > Faculty of Sciences (York) > Biology (York) The University of York > Faculty of Sciences (York) > Hull York Medical School (York) |
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Funding Information: |
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Depositing User: | Pure (York) | ||||||
Date Deposited: | 12 Jun 2018 11:20 | ||||||
Last Modified: | 07 Mar 2024 00:10 | ||||||
Published Version: | https://doi.org/10.15252/emmm.201708304 | ||||||
Status: | Published | ||||||
Refereed: | Yes | ||||||
Identification Number: | https://doi.org/10.15252/emmm.201708304 | ||||||
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