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 Lagos; Nicholas R. Lemoine; Prabhakar Rajan; Trevor A Graham; Claude Chelala; Kairbaan M Hodivala-Dilke; Ian Spendlove; Tyson V Sharp

doi:10.15252/emmm.201708304

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 journal › Article › peer-review

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.

Original language	English
Article number	e8304
Number of pages	18
Journal	EMBO Molecular Medicine
Volume	10
Issue number	7
Early online date	21 Jun 2018
DOIs	https://doi.org/10.15252/emmm.201708304
Publication status	Published - 1 Aug 2018

Bibliographical note

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

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Cite this

Bridge, K., Foxler, D. E., Foster, J. G., Grevitt, P., Curry, S., Shah, K. M., Davidson, K. M., Nagano, A., Gadaleta, E., Rhys, H. I., Kennedy, P. T., Hermida, M. A., Chang, T.-Y., Shaw, P. E., Reynolds, L. E., McKay, T. R., Wang, H.-W., Ribeiro, P. S., Plevin, M. J., ... Sharp, T. V. (2018). A HIF–LIMD1 negative feedback mechanism mitigates the pro‐tumorigenic effects of hypoxia. EMBO Molecular Medicine, 10(7), Article e8304. https://doi.org/10.15252/emmm.201708304

@article{9a0ea8746d59471e88443768ebb8ae4f,

title = "A HIF–LIMD1 negative feedback mechanism mitigates the pro‐tumorigenic effects of hypoxia",

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.",

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",

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

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doi = "10.15252/emmm.201708304",

language = "English",

volume = "10",

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Bridge, K, Foxler, DE, Foster, JG, Grevitt, P, Curry, S, Shah, KM, Davidson, KM, Nagano, A, Gadaleta, E, Rhys, HI, Kennedy, PT, Hermida, MA, Chang, T-Y, Shaw, PE, Reynolds, LE, McKay, TR, Wang, H-W, Ribeiro, PS, Plevin, MJ , Lagos, D, Lemoine, NR, Rajan, P, Graham, TA, Chelala, C, Hodivala-Dilke, KM, Spendlove, I & Sharp, TV 2018, 'A HIF–LIMD1 negative feedback mechanism mitigates the pro‐tumorigenic effects of hypoxia', EMBO Molecular Medicine, vol. 10, no. 7, e8304. https://doi.org/10.15252/emmm.201708304

TY - JOUR

T1 - A HIF–LIMD1 negative feedback mechanism mitigates the pro‐tumorigenic effects of hypoxia

AU - Bridge, Katherine

AU - Foxler, Daniel E

AU - Foster, John G

AU - Grevitt, Paul

AU - Curry, Sean

AU - Shah, Kunal M

AU - Davidson, Kathryn M

AU - Nagano, Ai

AU - Gadaleta, Emanuela

AU - Rhys, Hefin I.

AU - Kennedy, Paul T

AU - Hermida, Miguel A

AU - Chang, Ting-Yu

AU - Shaw, Peter E

AU - Reynolds, Louise E

AU - McKay, Tristan R.

AU - Wang, Hsei-Wei

AU - Ribeiro, Paulo S

AU - Plevin, Michael J

AU - Lagos, Dimitris

AU - Lemoine, Nicholas R.

AU - Rajan, Prabhakar

AU - Graham, Trevor A

AU - Chelala, Claude

AU - Hodivala-Dilke, Kairbaan M

AU - Spendlove, Ian

AU - Sharp, Tyson V

PY - 2018/8/1

Y1 - 2018/8/1

N2 - 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.

AB - 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.

KW - Adenocarcinoma/diagnosis

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Animals

KW - Carcinogenesis/genetics

KW - Cell Hypoxia/genetics

KW - Cell Line, Tumor

KW - Feedback, Physiological

KW - Female

KW - Gene Expression Regulation, Neoplastic

KW - Humans

KW - Hypoxia-Inducible Factor 1, alpha Subunit/genetics

KW - Intracellular Signaling Peptides and Proteins/genetics

KW - LIM Domain Proteins/genetics

KW - Lung Neoplasms/diagnosis

KW - Male

KW - Mice

KW - Middle Aged

KW - Prognosis

KW - Survival Analysis

KW - Vascular Endothelial Growth Factor A/genetics

UR - http://www.scopus.com/inward/record.url?scp=85051195960&partnerID=8YFLogxK

U2 - 10.15252/emmm.201708304

DO - 10.15252/emmm.201708304

M3 - Article

C2 - 29930174

SN - 1757-4676

VL - 10

JO - EMBO Molecular Medicine

JF - EMBO Molecular Medicine

IS - 7

M1 - e8304

ER -

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

Abstract

Bibliographical note

Keywords

Access to Document

Other files and links

Dimitris Lagos

Evaluating the mechanisms that drive the displacement of dsRNA-binding proteins from dsRNA

Characterisation of a new mechanism of regulation for HIFI and the hypexic response

Cite this

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

Abstract

Bibliographical note

Keywords

Access to Document

Other files and links

Profiles

Dimitris Lagos

Projects

Evaluating the mechanisms that drive the displacement of dsRNA-binding proteins from dsRNA

Characterisation of a new mechanism of regulation for HIFI and the hypexic response

Cite this