A HIF-LIMD1 negative feedback mechanism mitigates the pro-tumorigenic effects of hypoxia

Foxler, Daniel E. and Bridge, Katherine S. and Foster, John G. and Grevitt, Paul and Curry, Sean and Shah, Kunal M. and Davidson, Kathryn M. and Nagano, Ai and Gadaleta, Emanuela and Rhys, Hefin I. and Kennedy, Paul T. and Hermida, Miguel A. and Chang, Ting-Yu and Shaw, Peter E. and Reynolds, Louise E. and McKay, Tristan R. and Wang, Hsei- Wei and Ribeiro, Paulo S. and Plevin, Michael J. and Lagos, Dimitris and Lemoine, Nicholas R. and Rajan, Prabhakar and Graham, Trevor A. and Chelala, Claude and Hodivala-Dilke, Kairbaan M. and Spendlove, Ian and Sharp, Tyson V. (2018) A HIF-LIMD1 negative feedback mechanism mitigates the pro-tumorigenic effects of hypoxia. EMBO Molecular Medicine . e8304/1-e8304/18. ISSN 1757-4684

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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 β subunits. Prolonged HIF expression is a key contributor to cellular transformation, tumourigenesis 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.

Item Type: Article
RIS ID: https://nottingham-repository.worktribe.com/output/939782
Keywords: Adaptive hypoxic response; HIF-1; LIMD1; lung cancer; Tumour suppressor
Schools/Departments: University of Nottingham, UK > Faculty of Medicine and Health Sciences > School of Medicine > Division of Cancer and Stem Cells
University of Nottingham, UK > Faculty of Medicine and Health Sciences > School of Life Sciences
Identification Number: https://doi.org/10.15252/emmm.201708304
Depositing User: Spendlove, Ian
Date Deposited: 03 Aug 2018 13:55
Last Modified: 04 May 2020 19:41
URI: http://eprints.nottingham.ac.uk/id/eprint/53241

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