Nuclear IGF1R Interacts with Regulatory Regions of Chromatin to Promote RNA Polymerase II Recruitment and Gene Expression Associated with Advanced Tumor Stage
Internalization of ligand-activated type I IGF receptor (IGF1R) is followed by recycling to the plasma membrane, degradation or nuclear translocation. Nuclear IGF1R reportedly associates with clinical response to IGF1R inhibitory drugs, yet its role in the nucleus is poorly characterized. Here, we i...
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| Vydáno v: | Cancer research (Chicago, Ill.) Ročník 78; číslo 13; s. 3497 |
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| Hlavní autoři: | , , , , , , , , , , , , , , , , , |
| Médium: | Journal Article |
| Jazyk: | angličtina |
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United States
01.07.2018
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| ISSN: | 1538-7445, 1538-7445 |
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| Abstract | Internalization of ligand-activated type I IGF receptor (IGF1R) is followed by recycling to the plasma membrane, degradation or nuclear translocation. Nuclear IGF1R reportedly associates with clinical response to IGF1R inhibitory drugs, yet its role in the nucleus is poorly characterized. Here, we investigated the significance of nuclear IGF1R in clinical cancers and cell line models. In prostate cancers, IGF1R was predominantly membrane localized in benign glands, while malignant epithelium contained prominent internalized (nuclear/cytoplasmic) IGF1R, and nuclear IGF1R associated significantly with advanced tumor stage. Using ChIP-seq to assess global chromatin occupancy, we identified IGF1R-binding sites at or near transcription start sites of genes including
and
, most sites coinciding with occupancy by RNA polymerase II (RNAPol2) and histone marks of active enhancers/promoters. IGF1R was inducibly recruited to chromatin, directly binding DNA and interacting with RNAPol2 to upregulate expression of JUN and FAM21, shown to mediate tumor cell survival and IGF-induced migration. IGF1 also enriched RNAPol2 on promoters containing IGF1R-binding sites. These functions were inhibited by IGF1/II-neutralizing antibody xentuzumab (BI 836845), or by blocking receptor internalization. We detected IGF1R on
and
promoters in fresh prostate cancers that contained abundant nuclear IGF1R, with evidence of correlation between nuclear IGF1R content and JUN expression in malignant prostatic epithelium. Taken together, these data reveal previously unrecognized molecular mechanisms through which IGFs promote tumorigenesis, with implications for therapeutic evaluation of anti-IGF drugs.
These findings reveal a noncanonical nuclear role for IGF1R in tumorigenesis, with implications for therapeutic evaluation of IGF inhibitory drugs.
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| AbstractList | Internalization of ligand-activated type I IGF receptor (IGF1R) is followed by recycling to the plasma membrane, degradation or nuclear translocation. Nuclear IGF1R reportedly associates with clinical response to IGF1R inhibitory drugs, yet its role in the nucleus is poorly characterized. Here, we investigated the significance of nuclear IGF1R in clinical cancers and cell line models. In prostate cancers, IGF1R was predominantly membrane localized in benign glands, while malignant epithelium contained prominent internalized (nuclear/cytoplasmic) IGF1R, and nuclear IGF1R associated significantly with advanced tumor stage. Using ChIP-seq to assess global chromatin occupancy, we identified IGF1R-binding sites at or near transcription start sites of genes including JUN and FAM21, most sites coinciding with occupancy by RNA polymerase II (RNAPol2) and histone marks of active enhancers/promoters. IGF1R was inducibly recruited to chromatin, directly binding DNA and interacting with RNAPol2 to upregulate expression of JUN and FAM21, shown to mediate tumor cell survival and IGF-induced migration. IGF1 also enriched RNAPol2 on promoters containing IGF1R-binding sites. These functions were inhibited by IGF1/II-neutralizing antibody xentuzumab (BI 836845), or by blocking receptor internalization. We detected IGF1R on JUN and FAM21 promoters in fresh prostate cancers that contained abundant nuclear IGF1R, with evidence of correlation between nuclear IGF1R content and JUN expression in malignant prostatic epithelium. Taken together, these data reveal previously unrecognized molecular mechanisms through which IGFs promote tumorigenesis, with implications for therapeutic evaluation of anti-IGF drugs.Significance: These findings reveal a noncanonical nuclear role for IGF1R in tumorigenesis, with implications for therapeutic evaluation of IGF inhibitory drugs. Cancer Res; 78(13); 3497-509. ©2018 AACR.Internalization of ligand-activated type I IGF receptor (IGF1R) is followed by recycling to the plasma membrane, degradation or nuclear translocation. Nuclear IGF1R reportedly associates with clinical response to IGF1R inhibitory drugs, yet its role in the nucleus is poorly characterized. Here, we investigated the significance of nuclear IGF1R in clinical cancers and cell line models. In prostate cancers, IGF1R was predominantly membrane localized in benign glands, while malignant epithelium contained prominent internalized (nuclear/cytoplasmic) IGF1R, and nuclear IGF1R associated significantly with advanced tumor stage. Using ChIP-seq to assess global chromatin occupancy, we identified IGF1R-binding sites at or near transcription start sites of genes including JUN and FAM21, most sites coinciding with occupancy by RNA polymerase II (RNAPol2) and histone marks of active enhancers/promoters. IGF1R was inducibly recruited to chromatin, directly binding DNA and interacting with RNAPol2 to upregulate expression of JUN and FAM21, shown to mediate tumor cell survival and IGF-induced migration. IGF1 also enriched RNAPol2 on promoters containing IGF1R-binding sites. These functions were inhibited by IGF1/II-neutralizing antibody xentuzumab (BI 836845), or by blocking receptor internalization. We detected IGF1R on JUN and FAM21 promoters in fresh prostate cancers that contained abundant nuclear IGF1R, with evidence of correlation between nuclear IGF1R content and JUN expression in malignant prostatic epithelium. Taken together, these data reveal previously unrecognized molecular mechanisms through which IGFs promote tumorigenesis, with implications for therapeutic evaluation of anti-IGF drugs.Significance: These findings reveal a noncanonical nuclear role for IGF1R in tumorigenesis, with implications for therapeutic evaluation of IGF inhibitory drugs. Cancer Res; 78(13); 3497-509. ©2018 AACR. Internalization of ligand-activated type I IGF receptor (IGF1R) is followed by recycling to the plasma membrane, degradation or nuclear translocation. Nuclear IGF1R reportedly associates with clinical response to IGF1R inhibitory drugs, yet its role in the nucleus is poorly characterized. Here, we investigated the significance of nuclear IGF1R in clinical cancers and cell line models. In prostate cancers, IGF1R was predominantly membrane localized in benign glands, while malignant epithelium contained prominent internalized (nuclear/cytoplasmic) IGF1R, and nuclear IGF1R associated significantly with advanced tumor stage. Using ChIP-seq to assess global chromatin occupancy, we identified IGF1R-binding sites at or near transcription start sites of genes including and , most sites coinciding with occupancy by RNA polymerase II (RNAPol2) and histone marks of active enhancers/promoters. IGF1R was inducibly recruited to chromatin, directly binding DNA and interacting with RNAPol2 to upregulate expression of JUN and FAM21, shown to mediate tumor cell survival and IGF-induced migration. IGF1 also enriched RNAPol2 on promoters containing IGF1R-binding sites. These functions were inhibited by IGF1/II-neutralizing antibody xentuzumab (BI 836845), or by blocking receptor internalization. We detected IGF1R on and promoters in fresh prostate cancers that contained abundant nuclear IGF1R, with evidence of correlation between nuclear IGF1R content and JUN expression in malignant prostatic epithelium. Taken together, these data reveal previously unrecognized molecular mechanisms through which IGFs promote tumorigenesis, with implications for therapeutic evaluation of anti-IGF drugs. These findings reveal a noncanonical nuclear role for IGF1R in tumorigenesis, with implications for therapeutic evaluation of IGF inhibitory drugs. . |
| Author | Mills, Jack Bogenrieder, Thomas Aleksic, Tamara Taylor, Stephen Gray, Nicki Sanderson, Michael P Verrill, Clare Kumar, Rajeev Osher, Eliot Bryant, Richard J Hutchinson, Kathryn Han, Cheng Wu, Xiaoning Hamdy, Freddie C Lambert, Adam G Macaulay, Valentine M Rieunier, Guillaume Weyer-Czernilofsky, Ulrike |
| Author_xml | – sequence: 1 givenname: Tamara surname: Aleksic fullname: Aleksic, Tamara organization: Department of Oncology, University of Oxford, Oxford, United Kingdom – sequence: 2 givenname: Nicki surname: Gray fullname: Gray, Nicki organization: Computational Biology Research Group, University of Oxford, Weatherall Institute of Molecular Medicine, Oxford, United Kingdom – sequence: 3 givenname: Xiaoning surname: Wu fullname: Wu, Xiaoning organization: Department of Oncology, University of Oxford, Oxford, United Kingdom – sequence: 4 givenname: Guillaume surname: Rieunier fullname: Rieunier, Guillaume organization: Department of Oncology, University of Oxford, Oxford, United Kingdom – sequence: 5 givenname: Eliot surname: Osher fullname: Osher, Eliot organization: Department of Oncology, University of Oxford, Oxford, United Kingdom – sequence: 6 givenname: Jack orcidid: 0000-0002-1852-4596 surname: Mills fullname: Mills, Jack organization: Department of Oncology, University of Oxford, Oxford, United Kingdom – sequence: 7 givenname: Clare surname: Verrill fullname: Verrill, Clare organization: Department of Cellular Pathology, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, United Kingdom – sequence: 8 givenname: Richard J surname: Bryant fullname: Bryant, Richard J organization: Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom – sequence: 9 givenname: Cheng surname: Han fullname: Han, Cheng organization: Oxford Cancer and Haematology Centre, Oxford University Hospitals NHS Foundation Trust, Churchill Hospital, Oxford, United Kingdom – sequence: 10 givenname: Kathryn surname: Hutchinson fullname: Hutchinson, Kathryn organization: Department of Oncology, University of Oxford, Oxford, United Kingdom – sequence: 11 givenname: Adam G surname: Lambert fullname: Lambert, Adam G organization: Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom – sequence: 12 givenname: Rajeev surname: Kumar fullname: Kumar, Rajeev organization: Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom – sequence: 13 givenname: Freddie C surname: Hamdy fullname: Hamdy, Freddie C organization: Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom – sequence: 14 givenname: Ulrike surname: Weyer-Czernilofsky fullname: Weyer-Czernilofsky, Ulrike organization: Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria – sequence: 15 givenname: Michael P surname: Sanderson fullname: Sanderson, Michael P organization: Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria – sequence: 16 givenname: Thomas surname: Bogenrieder fullname: Bogenrieder, Thomas organization: Department of Urology, University Hospital Grosshadern, Ludwig-Maximilians-University, Marchioninistrasse, Munich, Germany – sequence: 17 givenname: Stephen surname: Taylor fullname: Taylor, Stephen organization: Computational Biology Research Group, University of Oxford, Weatherall Institute of Molecular Medicine, Oxford, United Kingdom – sequence: 18 givenname: Valentine M surname: Macaulay fullname: Macaulay, Valentine M email: valentine.macaulay@oncology.ox.ac.uk organization: Oxford Cancer and Haematology Centre, Oxford University Hospitals NHS Foundation Trust, Churchill Hospital, Oxford, United Kingdom |
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| SubjectTerms | Aged Cell Line, Tumor Cell Movement - genetics Cell Nucleus - pathology Cell Survival - genetics Chromatin - genetics Chromatin - metabolism Gene Expression Regulation, Neoplastic - genetics Humans Insulin-Like Growth Factor I - metabolism Intracellular Signaling Peptides and Proteins - genetics Intracellular Signaling Peptides and Proteins - metabolism Male Middle Aged Neoplasm Staging Promoter Regions, Genetic - genetics Prostatectomy Prostatic Neoplasms - genetics Prostatic Neoplasms - pathology Prostatic Neoplasms - surgery Proto-Oncogene Proteins c-jun - genetics Proto-Oncogene Proteins c-jun - metabolism Receptor, IGF Type 1 Receptors, Somatomedin - metabolism RNA Polymerase II - metabolism Signal Transduction - genetics Transcription Initiation Site Up-Regulation |
| Title | Nuclear IGF1R Interacts with Regulatory Regions of Chromatin to Promote RNA Polymerase II Recruitment and Gene Expression Associated with Advanced Tumor Stage |
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