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Hyperglycemia Promotes TMPRSS2-ERG Gene Fusion in Prostate Cancer Cells via Upregulating Insulin-Like Growth Factor-Binding Protein-2

BACKGROUND: Epidemiologic evidence shows that obesity is associated with a greater risk of aggressive prostate cancer (PCa) and PCa-specific mortality and this is observed mainly in men with the TMPRSS2-ERG gene fusion. Obesity is often associated with comorbid conditions such as type 2 diabetes and...

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Autores principales: Holly, Jeff M. P., Broadhurst, Jessica, Mansor, Rehanna, Bahl, Amit, Perks, Claire M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5681733/
https://www.ncbi.nlm.nih.gov/pubmed/29163372
http://dx.doi.org/10.3389/fendo.2017.00305
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author Holly, Jeff M. P.
Broadhurst, Jessica
Mansor, Rehanna
Bahl, Amit
Perks, Claire M.
author_facet Holly, Jeff M. P.
Broadhurst, Jessica
Mansor, Rehanna
Bahl, Amit
Perks, Claire M.
author_sort Holly, Jeff M. P.
collection PubMed
description BACKGROUND: Epidemiologic evidence shows that obesity is associated with a greater risk of aggressive prostate cancer (PCa) and PCa-specific mortality and this is observed mainly in men with the TMPRSS2-ERG gene fusion. Obesity is often associated with comorbid conditions such as type 2 diabetes and hyperglycemia: we investigated whether some of the exposures associated with disturbed metabolism can also affect the frequency of this gene fusion. METHODS: Fusion was induced in LNCaP PCa cells in normal or high levels of glucose, with or without insulin-like growth factor binding protein-2 (IGFBP-2) silenced or the presence of insulin-like growth factor-1 (IGF-I), insulin, or epidermal growth factor (EGF). RNA was extracted for analysis by nested PCR. Abundance of IGFBP-2, γH2AX, DNA-dependent protein kinase catalytic subunit (DNAPKcs), and β-actin were analyzed by Western immunoblotting. RESULTS: Our data suggest that hyperglycemia-induced IGFBP-2 increased the frequency of the gene fusion that was accompanied by decreased levels of DNAPKcs implying that they were mediated by alterations in the rate of repair of double-strand breaks. In contrast insulin, IGF-I and EGF all decreased gene fusion events. CONCLUSION: These novel observations may represent a further mechanism by which obesity can exert an effect aggravating PCa progression.
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spelling pubmed-56817332017-11-21 Hyperglycemia Promotes TMPRSS2-ERG Gene Fusion in Prostate Cancer Cells via Upregulating Insulin-Like Growth Factor-Binding Protein-2 Holly, Jeff M. P. Broadhurst, Jessica Mansor, Rehanna Bahl, Amit Perks, Claire M. Front Endocrinol (Lausanne) Endocrinology BACKGROUND: Epidemiologic evidence shows that obesity is associated with a greater risk of aggressive prostate cancer (PCa) and PCa-specific mortality and this is observed mainly in men with the TMPRSS2-ERG gene fusion. Obesity is often associated with comorbid conditions such as type 2 diabetes and hyperglycemia: we investigated whether some of the exposures associated with disturbed metabolism can also affect the frequency of this gene fusion. METHODS: Fusion was induced in LNCaP PCa cells in normal or high levels of glucose, with or without insulin-like growth factor binding protein-2 (IGFBP-2) silenced or the presence of insulin-like growth factor-1 (IGF-I), insulin, or epidermal growth factor (EGF). RNA was extracted for analysis by nested PCR. Abundance of IGFBP-2, γH2AX, DNA-dependent protein kinase catalytic subunit (DNAPKcs), and β-actin were analyzed by Western immunoblotting. RESULTS: Our data suggest that hyperglycemia-induced IGFBP-2 increased the frequency of the gene fusion that was accompanied by decreased levels of DNAPKcs implying that they were mediated by alterations in the rate of repair of double-strand breaks. In contrast insulin, IGF-I and EGF all decreased gene fusion events. CONCLUSION: These novel observations may represent a further mechanism by which obesity can exert an effect aggravating PCa progression. Frontiers Media S.A. 2017-11-06 /pmc/articles/PMC5681733/ /pubmed/29163372 http://dx.doi.org/10.3389/fendo.2017.00305 Text en Copyright © 2017 Holly, Broadhurst, Mansor, Bahl and Perks. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Endocrinology
Holly, Jeff M. P.
Broadhurst, Jessica
Mansor, Rehanna
Bahl, Amit
Perks, Claire M.
Hyperglycemia Promotes TMPRSS2-ERG Gene Fusion in Prostate Cancer Cells via Upregulating Insulin-Like Growth Factor-Binding Protein-2
title Hyperglycemia Promotes TMPRSS2-ERG Gene Fusion in Prostate Cancer Cells via Upregulating Insulin-Like Growth Factor-Binding Protein-2
title_full Hyperglycemia Promotes TMPRSS2-ERG Gene Fusion in Prostate Cancer Cells via Upregulating Insulin-Like Growth Factor-Binding Protein-2
title_fullStr Hyperglycemia Promotes TMPRSS2-ERG Gene Fusion in Prostate Cancer Cells via Upregulating Insulin-Like Growth Factor-Binding Protein-2
title_full_unstemmed Hyperglycemia Promotes TMPRSS2-ERG Gene Fusion in Prostate Cancer Cells via Upregulating Insulin-Like Growth Factor-Binding Protein-2
title_short Hyperglycemia Promotes TMPRSS2-ERG Gene Fusion in Prostate Cancer Cells via Upregulating Insulin-Like Growth Factor-Binding Protein-2
title_sort hyperglycemia promotes tmprss2-erg gene fusion in prostate cancer cells via upregulating insulin-like growth factor-binding protein-2
topic Endocrinology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5681733/
https://www.ncbi.nlm.nih.gov/pubmed/29163372
http://dx.doi.org/10.3389/fendo.2017.00305
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