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Selenium nanoparticles modulate histone methylation via lysine methyltransferase activity and S-adenosylhomocysteine depletion

BENOIT TOUBHANS, Nour Alkafri, Marcos Quintela Vazquez, David James, Caroline Bissardon, Salvatore Gazze, Franziska Knodel, Olivier Proux, Alexandra T. Gourlan, Philipp Rathert, Sylvain Bohic, Deya Gonzalez Orcid Logo, Lewis Francis Orcid Logo, Laurent Charlet, Steve Conlan Orcid Logo

Redox Biology, Volume: 61, Start page: 102641

Swansea University Authors: BENOIT TOUBHANS, Marcos Quintela Vazquez, David James, Salvatore Gazze, Deya Gonzalez Orcid Logo, Lewis Francis Orcid Logo, Steve Conlan Orcid Logo

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DOI (Published version): 10.1016/j.redox.2023.102641

Abstract

At physiological levels, the trace element selenium plays a key role in redox reactions through the incorporation of selenocysteine in antioxidant enzymes. Selenium has also been evaluated as a potential anti-cancer agent, where selenium nanoparticles have proven effective, and are well tolerated in...

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Published in: Redox Biology
ISSN: 2213-2317
Published: Elsevier BV 2023
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URI: https://cronfa.swan.ac.uk/Record/cronfa62755
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Selenium has also been evaluated as a potential anti-cancer agent, where selenium nanoparticles have proven effective, and are well tolerated in vivo at doses that are toxic as soluble Se. The use of such nanoparticles, coated with either serum albumin or the naturally occurring alkaline polysaccharide chitosan, also serves to enhance biocompatibility and bioavailability. Here we demonstrate a novel role for selenium in regulating histone methylation in ovarian cancer cell models treated with inorganic selenium nanoparticles coated with serum albumin or chitosan. As well as inducing thioredoxin reductase expression, ROS activity and cancer cell cytotoxicity, coated nanoparticles caused significant increases in histone methylation. Specifically, selenium nanoparticles triggered an increase in the methylation of histone 3 at lysines K9 and K27, histone marks involved in both the activation and repression of gene expression, thus suggesting a fundamental role for selenium in these epigenetic processes. This direct function was confirmed using chemical inhibitors of the histone lysine methyltransferases EZH2 (H3K27) and G9a/EHMT2 (H3K9), both of which blocked the effect of selenium on histone methylation. This novel role for selenium supports a distinct function in histone methylation that occurs due to a decrease in S-adenosylhomocysteine, an endogenous inhibitor of lysine methyltransferases, the metabolic product of methyl-group transfer from S-adenosylmethionine in the one-carbon metabolism pathway. These observations provide important new insights into the action of selenium nanoparticles. It is now important to consider both the classic antioxidant and novel histone methylation effects of this key redox element in its development in cancer therapy and other applications.</abstract><type>Journal Article</type><journal>Redox Biology</journal><volume>61</volume><journalNumber/><paginationStart>102641</paginationStart><paginationEnd/><publisher>Elsevier BV</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint>2213-2317</issnPrint><issnElectronic/><keywords/><publishedDay>1</publishedDay><publishedMonth>5</publishedMonth><publishedYear>2023</publishedYear><publishedDate>2023-05-01</publishedDate><doi>10.1016/j.redox.2023.102641</doi><url/><notes/><college>COLLEGE NANME</college><CollegeCode>COLLEGE CODE</CollegeCode><institution>Swansea University</institution><apcterm>SU College/Department paid the OA fee</apcterm><funders>Benoit Toubhans received a scholarship co-funded by the Université Grenoble Alpes and Swansea University. Nour Al Kafri received a postgraduate development fellowship from the Council for At-Risk Academics (CARA). We recognise CEMHTI (Orleans, France, ANR-13-BS080012-01) and Labex OSUG@2020 (Grenoble, France, ANR-10- LABX-0056), FAME-UHD (EquipEx (EcoX, ANR-10- EQPX-27-01)) for beamtime. We thank Drs L. Sauzéat, S. Bouchet and Pr. L.H. Winkel, ETH Zürich, for ICPMS and speciation analysis. The electron microscope image was supported by the Rhône-Alpes Region, FRM, FEDER, CNRS, CEA, the University Grenoble Alpes, EMBL, GIS-IBISA, the Grenoble Instruct-ERIC Centre (ISBG: UMS 3518 CNRS-CEA-UGA-EMBL) with support from FRISBI (ANR-10-INSB-05-02) and GRAL (ANR-10-LABX-49-01) within the Grenoble Partnership for Structural Biology (PSB) platform (D. Fenel, C. Moriscot, B. Gallet and G. Schoen (PSB, ISBG, UMS 3518)). Part of this work was performed on the AccelerateAI facility, part-funded by the European Regional Development Fund through the Welsh Government via Ser Cymru.</funders><projectreference/><lastEdited>2023-09-13T14:54:25.8467495</lastEdited><Created>2023-02-26T14:58:42.0061340</Created><path><level id="1">Faculty of Medicine, Health and Life Sciences</level><level id="2">Swansea University Medical School - Medicine</level></path><authors><author><firstname>BENOIT</firstname><surname>TOUBHANS</surname><order>1</order></author><author><firstname>Nour</firstname><surname>Alkafri</surname><order>2</order></author><author><firstname>Marcos</firstname><surname>Quintela Vazquez</surname><order>3</order></author><author><firstname>David</firstname><surname>James</surname><orcid/><order>4</order></author><author><firstname>Caroline</firstname><surname>Bissardon</surname><order>5</order></author><author><firstname>Salvatore</firstname><surname>Gazze</surname><order>6</order></author><author><firstname>Franziska</firstname><surname>Knodel</surname><order>7</order></author><author><firstname>Olivier</firstname><surname>Proux</surname><order>8</order></author><author><firstname>Alexandra T.</firstname><surname>Gourlan</surname><order>9</order></author><author><firstname>Philipp</firstname><surname>Rathert</surname><order>10</order></author><author><firstname>Sylvain</firstname><surname>Bohic</surname><order>11</order></author><author><firstname>Deya</firstname><surname>Gonzalez</surname><orcid>0000-0002-1838-6752</orcid><order>12</order></author><author><firstname>Lewis</firstname><surname>Francis</surname><orcid>0000-0002-7803-7714</orcid><order>13</order></author><author><firstname>Laurent</firstname><surname>Charlet</surname><order>14</order></author><author><firstname>Steve</firstname><surname>Conlan</surname><orcid>0000-0002-2562-3461</orcid><order>15</order></author></authors><documents><document><filename>62755__26677__010fa56726c7451d8eced2fcec2dfaab.pdf</filename><originalFilename>62755_VoR.pdf</originalFilename><uploaded>2023-02-27T11:59:24.6277662</uploaded><type>Output</type><contentLength>8920712</contentLength><contentType>application/pdf</contentType><version>Version of Record</version><cronfaStatus>true</cronfaStatus><documentNotes>© 2023 The Authors. 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spelling v2 62755 2023-02-26 Selenium nanoparticles modulate histone methylation via lysine methyltransferase activity and S-adenosylhomocysteine depletion e44b952350e531414d9288079b9a7c12 BENOIT TOUBHANS BENOIT TOUBHANS true false 29d006fa16d293ca29762fce9c356f8e Marcos Quintela Vazquez Marcos Quintela Vazquez true false 31b39419835be9525450cf1420e63996 David James David James true false 586f1f49652b97c5c3ab99a45a1c58bf Salvatore Gazze Salvatore Gazze true false bafdf635eb81280304eedf4b18e65d4e 0000-0002-1838-6752 Deya Gonzalez Deya Gonzalez true false 10f61f9c1248951c1a33f6a89498f37d 0000-0002-7803-7714 Lewis Francis Lewis Francis true false 0bb6bd247e32fb4249de62c0013b51cb 0000-0002-2562-3461 Steve Conlan Steve Conlan true false 2023-02-26 At physiological levels, the trace element selenium plays a key role in redox reactions through the incorporation of selenocysteine in antioxidant enzymes. Selenium has also been evaluated as a potential anti-cancer agent, where selenium nanoparticles have proven effective, and are well tolerated in vivo at doses that are toxic as soluble Se. The use of such nanoparticles, coated with either serum albumin or the naturally occurring alkaline polysaccharide chitosan, also serves to enhance biocompatibility and bioavailability. Here we demonstrate a novel role for selenium in regulating histone methylation in ovarian cancer cell models treated with inorganic selenium nanoparticles coated with serum albumin or chitosan. As well as inducing thioredoxin reductase expression, ROS activity and cancer cell cytotoxicity, coated nanoparticles caused significant increases in histone methylation. Specifically, selenium nanoparticles triggered an increase in the methylation of histone 3 at lysines K9 and K27, histone marks involved in both the activation and repression of gene expression, thus suggesting a fundamental role for selenium in these epigenetic processes. This direct function was confirmed using chemical inhibitors of the histone lysine methyltransferases EZH2 (H3K27) and G9a/EHMT2 (H3K9), both of which blocked the effect of selenium on histone methylation. This novel role for selenium supports a distinct function in histone methylation that occurs due to a decrease in S-adenosylhomocysteine, an endogenous inhibitor of lysine methyltransferases, the metabolic product of methyl-group transfer from S-adenosylmethionine in the one-carbon metabolism pathway. These observations provide important new insights into the action of selenium nanoparticles. It is now important to consider both the classic antioxidant and novel histone methylation effects of this key redox element in its development in cancer therapy and other applications. Journal Article Redox Biology 61 102641 Elsevier BV 2213-2317 1 5 2023 2023-05-01 10.1016/j.redox.2023.102641 COLLEGE NANME COLLEGE CODE Swansea University SU College/Department paid the OA fee Benoit Toubhans received a scholarship co-funded by the Université Grenoble Alpes and Swansea University. Nour Al Kafri received a postgraduate development fellowship from the Council for At-Risk Academics (CARA). We recognise CEMHTI (Orleans, France, ANR-13-BS080012-01) and Labex OSUG@2020 (Grenoble, France, ANR-10- LABX-0056), FAME-UHD (EquipEx (EcoX, ANR-10- EQPX-27-01)) for beamtime. We thank Drs L. Sauzéat, S. Bouchet and Pr. L.H. Winkel, ETH Zürich, for ICPMS and speciation analysis. The electron microscope image was supported by the Rhône-Alpes Region, FRM, FEDER, CNRS, CEA, the University Grenoble Alpes, EMBL, GIS-IBISA, the Grenoble Instruct-ERIC Centre (ISBG: UMS 3518 CNRS-CEA-UGA-EMBL) with support from FRISBI (ANR-10-INSB-05-02) and GRAL (ANR-10-LABX-49-01) within the Grenoble Partnership for Structural Biology (PSB) platform (D. Fenel, C. Moriscot, B. Gallet and G. Schoen (PSB, ISBG, UMS 3518)). Part of this work was performed on the AccelerateAI facility, part-funded by the European Regional Development Fund through the Welsh Government via Ser Cymru. 2023-09-13T14:54:25.8467495 2023-02-26T14:58:42.0061340 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine BENOIT TOUBHANS 1 Nour Alkafri 2 Marcos Quintela Vazquez 3 David James 4 Caroline Bissardon 5 Salvatore Gazze 6 Franziska Knodel 7 Olivier Proux 8 Alexandra T. Gourlan 9 Philipp Rathert 10 Sylvain Bohic 11 Deya Gonzalez 0000-0002-1838-6752 12 Lewis Francis 0000-0002-7803-7714 13 Laurent Charlet 14 Steve Conlan 0000-0002-2562-3461 15 62755__26677__010fa56726c7451d8eced2fcec2dfaab.pdf 62755_VoR.pdf 2023-02-27T11:59:24.6277662 Output 8920712 application/pdf Version of Record true © 2023 The Authors. This is an open access article under the CC BY license true eng http://creativecommons.org/licenses/by/4.0/
title Selenium nanoparticles modulate histone methylation via lysine methyltransferase activity and S-adenosylhomocysteine depletion
spellingShingle Selenium nanoparticles modulate histone methylation via lysine methyltransferase activity and S-adenosylhomocysteine depletion
BENOIT TOUBHANS
Marcos Quintela Vazquez
David James
Salvatore Gazze
Deya Gonzalez
Lewis Francis
Steve Conlan
title_short Selenium nanoparticles modulate histone methylation via lysine methyltransferase activity and S-adenosylhomocysteine depletion
title_full Selenium nanoparticles modulate histone methylation via lysine methyltransferase activity and S-adenosylhomocysteine depletion
title_fullStr Selenium nanoparticles modulate histone methylation via lysine methyltransferase activity and S-adenosylhomocysteine depletion
title_full_unstemmed Selenium nanoparticles modulate histone methylation via lysine methyltransferase activity and S-adenosylhomocysteine depletion
title_sort Selenium nanoparticles modulate histone methylation via lysine methyltransferase activity and S-adenosylhomocysteine depletion
author_id_str_mv e44b952350e531414d9288079b9a7c12
29d006fa16d293ca29762fce9c356f8e
31b39419835be9525450cf1420e63996
586f1f49652b97c5c3ab99a45a1c58bf
bafdf635eb81280304eedf4b18e65d4e
10f61f9c1248951c1a33f6a89498f37d
0bb6bd247e32fb4249de62c0013b51cb
author_id_fullname_str_mv e44b952350e531414d9288079b9a7c12_***_BENOIT TOUBHANS
29d006fa16d293ca29762fce9c356f8e_***_Marcos Quintela Vazquez
31b39419835be9525450cf1420e63996_***_David James
586f1f49652b97c5c3ab99a45a1c58bf_***_Salvatore Gazze
bafdf635eb81280304eedf4b18e65d4e_***_Deya Gonzalez
10f61f9c1248951c1a33f6a89498f37d_***_Lewis Francis
0bb6bd247e32fb4249de62c0013b51cb_***_Steve Conlan
author BENOIT TOUBHANS
Marcos Quintela Vazquez
David James
Salvatore Gazze
Deya Gonzalez
Lewis Francis
Steve Conlan
author2 BENOIT TOUBHANS
Nour Alkafri
Marcos Quintela Vazquez
David James
Caroline Bissardon
Salvatore Gazze
Franziska Knodel
Olivier Proux
Alexandra T. Gourlan
Philipp Rathert
Sylvain Bohic
Deya Gonzalez
Lewis Francis
Laurent Charlet
Steve Conlan
format Journal article
container_title Redox Biology
container_volume 61
container_start_page 102641
publishDate 2023
institution Swansea University
issn 2213-2317
doi_str_mv 10.1016/j.redox.2023.102641
publisher Elsevier BV
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
document_store_str 1
active_str 0
description At physiological levels, the trace element selenium plays a key role in redox reactions through the incorporation of selenocysteine in antioxidant enzymes. Selenium has also been evaluated as a potential anti-cancer agent, where selenium nanoparticles have proven effective, and are well tolerated in vivo at doses that are toxic as soluble Se. The use of such nanoparticles, coated with either serum albumin or the naturally occurring alkaline polysaccharide chitosan, also serves to enhance biocompatibility and bioavailability. Here we demonstrate a novel role for selenium in regulating histone methylation in ovarian cancer cell models treated with inorganic selenium nanoparticles coated with serum albumin or chitosan. As well as inducing thioredoxin reductase expression, ROS activity and cancer cell cytotoxicity, coated nanoparticles caused significant increases in histone methylation. Specifically, selenium nanoparticles triggered an increase in the methylation of histone 3 at lysines K9 and K27, histone marks involved in both the activation and repression of gene expression, thus suggesting a fundamental role for selenium in these epigenetic processes. This direct function was confirmed using chemical inhibitors of the histone lysine methyltransferases EZH2 (H3K27) and G9a/EHMT2 (H3K9), both of which blocked the effect of selenium on histone methylation. This novel role for selenium supports a distinct function in histone methylation that occurs due to a decrease in S-adenosylhomocysteine, an endogenous inhibitor of lysine methyltransferases, the metabolic product of methyl-group transfer from S-adenosylmethionine in the one-carbon metabolism pathway. These observations provide important new insights into the action of selenium nanoparticles. It is now important to consider both the classic antioxidant and novel histone methylation effects of this key redox element in its development in cancer therapy and other applications.
published_date 2023-05-01T14:54:27Z
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