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 |
---|---|
Authors/Creators: |
|
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: |
|
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) |
Funding Information: | Funder Grant number UNSPECIFIED BB/N018818/1 BBSRC (BIOTECHNOLOGY AND BIOLOGICAL SCIENCES RESEARCH COUNCIL) BB/M000206/1 |
Depositing User: | Pure (York) |
Date Deposited: | 12 Jun 2018 11:20 |
Last Modified: | 03 Nov 2024 01:22 |
Published Version: | https://doi.org/10.15252/emmm.201708304 |
Status: | Published |
Refereed: | Yes |
Identification Number: | 10.15252/emmm.201708304 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:131872 |