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

Katherine Bridge, Daniel E Foxler, 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 LagosNicholas R. Lemoine, Prabhakar Rajan, Trevor A Graham, Claude Chelala, Kairbaan M Hodivala-Dilke, Ian Spendlove, Tyson V Sharp

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Article numbere8304
Number of pages18
JournalEMBO Molecular Medicine
Issue number7
Early online date21 Jun 2018
Publication statusPublished - 1 Aug 2018

Bibliographical note

© 2018, The Author(s).


  • 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

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