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

Foxler, Daniel E.; Bridge, Katherine S.; Foster, John G.; Grevitt, Paul; Curry, Sean; Shah, Kunal M.; Davidson, Kathryn M.; Nagano, Ai; Gadaleta, Emanuela; Rhys, Hefin I.; Kennedy, Paul T.; Hermida, Miguel A.; Chang, Ting-Yu; Shaw, Peter E.; Reynolds, Louise E.; McKay, Tristan R.; Wang, Hsei- Wei; Ribeiro, Paulo S.; Plevin, Michael J.; Lagos, Dimitris; Lemoine, Nicholas R.; Rajan, Prabhakar; Graham, Trevor A.; Chelala, Claude; Hodivala-Dilke, Kairbaan M.; Spendlove, Ian; Sharp, Tyson V.


Daniel E. Foxler

Katherine S. Bridge

John G. Foster

Paul Grevitt

Sean Curry

Kunal M. Shah

Kathryn M. Davidson

Ai Nagano

Emanuela Gadaleta

Hefin I. Rhys

Paul T. Kennedy

Miguel A. Hermida

Ting-Yu Chang

Peter E. Shaw

Louise E. Reynolds

Tristan R. McKay

Hsei- Wei Wang

Paulo S. Ribeiro

Michael J. Plevin

Dimitris Lagos

Nicholas R. Lemoine

Prabhakar Rajan

Trevor A. Graham

Claude Chelala

Kairbaan M. Hodivala-Dilke

Tyson V. Sharp


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-? and ? 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-? subunit. Here, we identify LIMD1 as a HIF-1 target gene, which mediates a previously uncharacterised, negative regulatory feedback mechanism for hypoxic HIF-? degradation by modulating PHD2-LIMD1- VHL complex formation. Hypoxic induction of LIMD1 expression results in increased HIF-? 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.


Foxler, D. E., Bridge, K. S., Foster, J. G., Grevitt, P., Curry, S., Shah, K. M., …Sharp, T. V. (in press). A HIF-LIMD1 negative feedback mechanism mitigates the pro-tumorigenic effects of hypoxia. EMBO Molecular Medicine, Article e8304.

Journal Article Type Article
Acceptance Date May 28, 2018
Online Publication Date Jun 21, 2018
Deposit Date Aug 3, 2018
Publicly Available Date Aug 3, 2018
Journal EMBO Molecular Medicine
Print ISSN 1757-4676
Electronic ISSN 1757-4684
Publisher Wiley
Peer Reviewed Peer Reviewed
Article Number e8304
Keywords Adaptive hypoxic response; HIF-1; LIMD1; lung cancer; Tumour suppressor
Public URL
Publisher URL


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