Quantitative profiling of chromatome dynamics reveals a novel role for HP1BP3 in hypoxia-induced oncogenesis
In contrast to the intensely studied genetic and epigenetic changes that induce host cell transformation to initiate tumor development, those that promote the malignant progression of cancer remain poorly defined. As emerging evidence suggests that the hypoxic tumor microenvironment could re-model t...
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sg-ntu-dr.10356-808522023-02-28T17:00:54Z Quantitative profiling of chromatome dynamics reveals a novel role for HP1BP3 in hypoxia-induced oncogenesis Lim, Sai Kiang Tam, James P. Sze, Siu Kwan Dutta, Bamaprasad Yan, Ren School of Biological Sciences DRNTU::Science::Biological sciences::Molecular biology In contrast to the intensely studied genetic and epigenetic changes that induce host cell transformation to initiate tumor development, those that promote the malignant progression of cancer remain poorly defined. As emerging evidence suggests that the hypoxic tumor microenvironment could re-model the chromatin-associated proteome (chromatome) to induce epigenetic changes and alter gene expression in cancer cells, we hypothesized that hypoxia-driven evolution of the chromatome promotes malignant changes and the development of therapy resistance in tumor cells. To test this hypothesis, we isolated chromatins from tumor cells treated with varying conditions of normoxia, hypoxia, and re-oxygenation and then partially digested them with DNase I and analyzed them for changes in euchromatin- and heterochromatin-associated proteins using an iTRAQ-based quantitative proteomic approach. We identified a total of 1446 proteins with a high level of confidence, including 819 proteins that were observed to change their chromatin association topology under hypoxic conditions. These hypoxia-sensitive proteins included key mediators of chromatin organization, transcriptional regulation, and DNA repair. Furthermore, our proteomic and functional experiments revealed a novel role for the chromatin organizer protein HP1BP3 in mediating chromatin condensation during hypoxia, leading to increased tumor cell viability, radio-resistance, chemo-resistance, and self-renewal. Taken together, our findings indicate that HP1BP3 is a key mediator of tumor progression and cancer cell acquisition of therapy-resistant traits, and thus might represent a novel therapeutic target in a range of human malignancies. NMRC (Natl Medical Research Council, S’pore) Accepted version 2015-07-01T04:37:05Z 2019-12-06T14:15:53Z 2015-07-01T04:37:05Z 2019-12-06T14:15:53Z 2014 2014 Journal Article Dutta, B., Yan, R., Lim, S. K., Tam, J. P., & Sze, S. K. (2014). Quantitative profiling of chromatome dynamics reveals a novel role for HP1BP3 in hypoxia-induced oncogenesis. Molecular & cellular proteomics, 13(12), 3236-3249. https://hdl.handle.net/10356/80852 http://hdl.handle.net/10220/26165 10.1074/mcp.M114.038232 25100860 en Molecular & cellular proteomics © 2014 American Society for Biochemistry and Molecular Biology. This is the author created version of a work that has been peer reviewed and accepted for publication by Molecular & Cellular Proteomics, American Society for Biochemistry and Molecular Biology. It incorporates referee’s comments but changes resulting from the publishing process, such as copyediting, structural formatting, may not be reflected in this document. The published version is available at: [http://dx.doi.org/10.1074/mcp.M114.038232]. application/pdf |
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DRNTU::Science::Biological sciences::Molecular biology Lim, Sai Kiang Tam, James P. Sze, Siu Kwan Dutta, Bamaprasad Yan, Ren Quantitative profiling of chromatome dynamics reveals a novel role for HP1BP3 in hypoxia-induced oncogenesis |
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In contrast to the intensely studied genetic and epigenetic changes that induce host cell transformation to initiate tumor development, those that promote the malignant progression of cancer remain poorly defined. As emerging evidence suggests that the hypoxic tumor microenvironment could re-model the chromatin-associated proteome (chromatome) to induce epigenetic changes and alter gene expression in cancer cells, we hypothesized that hypoxia-driven evolution of the chromatome promotes malignant changes and the development of therapy resistance in tumor cells. To test this hypothesis, we isolated chromatins from tumor cells treated with varying conditions of normoxia, hypoxia, and re-oxygenation and then partially digested them with DNase I and analyzed them for changes in euchromatin- and heterochromatin-associated proteins using an iTRAQ-based quantitative proteomic approach. We identified a total of 1446 proteins with a high level of confidence, including 819 proteins that were observed to change their chromatin association topology under hypoxic conditions. These hypoxia-sensitive proteins included key mediators of chromatin organization, transcriptional regulation, and DNA repair. Furthermore, our proteomic and functional experiments revealed a novel role for the chromatin organizer protein HP1BP3 in mediating chromatin condensation during hypoxia, leading to increased tumor cell viability, radio-resistance, chemo-resistance, and self-renewal. Taken together, our findings indicate that HP1BP3 is a key mediator of tumor progression and cancer cell acquisition of therapy-resistant traits, and thus might represent a novel therapeutic target in a range of human malignancies. |
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School of Biological Sciences |
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School of Biological Sciences Lim, Sai Kiang Tam, James P. Sze, Siu Kwan Dutta, Bamaprasad Yan, Ren |
format |
Article |
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Lim, Sai Kiang Tam, James P. Sze, Siu Kwan Dutta, Bamaprasad Yan, Ren |
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Lim, Sai Kiang |
title |
Quantitative profiling of chromatome dynamics reveals a novel role for HP1BP3 in hypoxia-induced oncogenesis |
title_short |
Quantitative profiling of chromatome dynamics reveals a novel role for HP1BP3 in hypoxia-induced oncogenesis |
title_full |
Quantitative profiling of chromatome dynamics reveals a novel role for HP1BP3 in hypoxia-induced oncogenesis |
title_fullStr |
Quantitative profiling of chromatome dynamics reveals a novel role for HP1BP3 in hypoxia-induced oncogenesis |
title_full_unstemmed |
Quantitative profiling of chromatome dynamics reveals a novel role for HP1BP3 in hypoxia-induced oncogenesis |
title_sort |
quantitative profiling of chromatome dynamics reveals a novel role for hp1bp3 in hypoxia-induced oncogenesis |
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2015 |
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https://hdl.handle.net/10356/80852 http://hdl.handle.net/10220/26165 |
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1759852938625286144 |