A HIF–LIMD1 negative feedback mechanism mitigates the pro‐tumorigenic effects of hypoxia. Issue 8 (21st June 2018)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: EMBO molecular medicine. Volume 10:Issue 8(2018)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2018-06-21
• Subjects: adaptive hypoxic response -- HIF‐1 -- LIMD1 -- lung cancer -- tumour suppressor; Molecular biology -- Periodicals; Medical genetics -- Periodicals; Pathology, Molecular -- Periodicals; 616.04205
• DOI: 10.15252/emmm.201708304
• Languages: English
• ISSNs: 1757-4676

Abstract

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. Synopsis: This study identifies the tumour suppressor LIMD1 as a facilitator of an adaptive cellular response to hypoxia. Under hypoxic conditions, LIMD1 expression is induced, facilitating degradation of HIF, limiting HIF transcriptional activity and mitigating its pro‐tumorigenic effects. The LIMD1 promoter contains a hypoxia responsive element (HRE) and its expression is induced under hypoxic conditions driving increased HIF degradation via the PHD/VHL axis. HIF protein stability and transcriptional activity are reduced under chronic hypoxic conditions by LIMD1. Aberration of the LIMD1‐dependent hypoxic negative feedback loop causes larger and more vascularised tumours to grow in vivo . LIMD1 is lost in 47% of adenocarcinoma driving a hypoxic gene signature that serves as a negative prognostic indicator. Abstract : This study identifies the tumour suppressor LIMD1 as a facilitator of an adaptive cellular response to hypoxia. Under hypoxic conditions, LIMD1 expression is induced, facilitating degradation of HIF, limiting HIF transcriptional activity and mitigating its pro‐tumorigenic effects.