MTOR modulation induces selective perturbations in histone methylation which influence the anti-proliferative effects of mTOR inhibitors

Emerging data suggest a significant cross-talk between metabolic and epigenetic programs. However, the relationship between the mechanistic target of rapamycin (mTOR), which is a pivotal metabolic regulator, and epigenetic modifications remains poorly understood. Our results show that mTORC1 activat...

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Main Authors: Kim, HaEun, Lebeau, Benjamin, Papadopoli, David, Jovanovic, Predrag, Russo, Mariana, Avizonis, Daina, Morita, Masahiro, Afzali, Farzaneh, Ursini-Siegel, Josie, Postovit, Lynne-Marie, Witcher, Michael, Topisirovic, Ivan
Other Authors: School of Biological Sciences
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Language:English
Published: 2024
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Online Access:https://hdl.handle.net/10356/178388
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spelling sg-ntu-dr.10356-1783882024-06-24T15:32:11Z MTOR modulation induces selective perturbations in histone methylation which influence the anti-proliferative effects of mTOR inhibitors Kim, HaEun Lebeau, Benjamin Papadopoli, David Jovanovic, Predrag Russo, Mariana Avizonis, Daina Morita, Masahiro Afzali, Farzaneh Ursini-Siegel, Josie Postovit, Lynne-Marie Witcher, Michael Topisirovic, Ivan School of Biological Sciences Medicine, Health and Life Sciences Epigenetics Molecular biology Emerging data suggest a significant cross-talk between metabolic and epigenetic programs. However, the relationship between the mechanistic target of rapamycin (mTOR), which is a pivotal metabolic regulator, and epigenetic modifications remains poorly understood. Our results show that mTORC1 activation caused by the abrogation of its negative regulator tuberous sclerosis complex 2 (TSC2) coincides with increased levels of the histone modification H3K27me3 but not H3K4me3 or H3K9me3. This selective H3K27me3 induction was mediated via 4E-BP-dependent increase in EZH2 protein levels. Surprisingly, mTOR inhibition also selectively induced H3K27me3. This was independent of TSC2, and was paralleled by reduced EZH2 and increased EZH1 protein levels. Notably, the ability of mTOR inhibitors to induce H3K27me3 levels was positively correlated with their anti-proliferative effects. Collectively, our findings demonstrate that both activation and inhibition of mTOR selectively increase H3K27me3 by distinct mechanisms, whereby the induction of H3K27me3 may potentiate the anti-proliferative effects of mTOR inhibitors. Published version This research was funded by the Terry Fox Foundation (TFF) Oncometabolism Team Grant TFF-242122 to I.T. and Canadian Institutes for Health Research (CIHR) PJT-183843 to I.T. H.K. and P.J. are supported by Fonds de Recherche du Que´ bec – Sante´ (FRQS) Fellowships. D.P. is supported by CIHR Postdoctoral Fellowship (MFE-171312) and Cancer Research Society (CRS) The Next Generation of Scientists Award (NGS). I.T. is supported by FRQS Senior Investigator award. M.W. is supported by the CIHR, CRS and holds a salary award from FRQS. J.U.-S. is supported by CIHR PJT-103526. L.-M.P. is supported by the Canadian Cancer Society Research Institute (CCSRI) Innovation Grants. Metabolic analysis was performed at the Rosalind and Morris Goodman Cancer Research Centre’s Metabolomics Core Facility, which is supported by the Canada Foundation for Innovation, the Dr. John R. and Clara M. Fraser Memorial Trust, the Terry Fox Foundation (TFF Oncometabolism Team Grant; TFF-242122), and McGill University. 2024-06-18T00:51:23Z 2024-06-18T00:51:23Z 2024 Journal Article Kim, H., Lebeau, B., Papadopoli, D., Jovanovic, P., Russo, M., Avizonis, D., Morita, M., Afzali, F., Ursini-Siegel, J., Postovit, L., Witcher, M. & Topisirovic, I. (2024). MTOR modulation induces selective perturbations in histone methylation which influence the anti-proliferative effects of mTOR inhibitors. IScience, 27(3), 109188-. https://dx.doi.org/10.1016/j.isci.2024.109188 2589-0042 https://hdl.handle.net/10356/178388 10.1016/j.isci.2024.109188 38433910 2-s2.0-85185812639 3 27 109188 en iScience © 2024 The Author(s). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). application/pdf
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic Medicine, Health and Life Sciences
Epigenetics
Molecular biology
spellingShingle Medicine, Health and Life Sciences
Epigenetics
Molecular biology
Kim, HaEun
Lebeau, Benjamin
Papadopoli, David
Jovanovic, Predrag
Russo, Mariana
Avizonis, Daina
Morita, Masahiro
Afzali, Farzaneh
Ursini-Siegel, Josie
Postovit, Lynne-Marie
Witcher, Michael
Topisirovic, Ivan
MTOR modulation induces selective perturbations in histone methylation which influence the anti-proliferative effects of mTOR inhibitors
description Emerging data suggest a significant cross-talk between metabolic and epigenetic programs. However, the relationship between the mechanistic target of rapamycin (mTOR), which is a pivotal metabolic regulator, and epigenetic modifications remains poorly understood. Our results show that mTORC1 activation caused by the abrogation of its negative regulator tuberous sclerosis complex 2 (TSC2) coincides with increased levels of the histone modification H3K27me3 but not H3K4me3 or H3K9me3. This selective H3K27me3 induction was mediated via 4E-BP-dependent increase in EZH2 protein levels. Surprisingly, mTOR inhibition also selectively induced H3K27me3. This was independent of TSC2, and was paralleled by reduced EZH2 and increased EZH1 protein levels. Notably, the ability of mTOR inhibitors to induce H3K27me3 levels was positively correlated with their anti-proliferative effects. Collectively, our findings demonstrate that both activation and inhibition of mTOR selectively increase H3K27me3 by distinct mechanisms, whereby the induction of H3K27me3 may potentiate the anti-proliferative effects of mTOR inhibitors.
author2 School of Biological Sciences
author_facet School of Biological Sciences
Kim, HaEun
Lebeau, Benjamin
Papadopoli, David
Jovanovic, Predrag
Russo, Mariana
Avizonis, Daina
Morita, Masahiro
Afzali, Farzaneh
Ursini-Siegel, Josie
Postovit, Lynne-Marie
Witcher, Michael
Topisirovic, Ivan
format Article
author Kim, HaEun
Lebeau, Benjamin
Papadopoli, David
Jovanovic, Predrag
Russo, Mariana
Avizonis, Daina
Morita, Masahiro
Afzali, Farzaneh
Ursini-Siegel, Josie
Postovit, Lynne-Marie
Witcher, Michael
Topisirovic, Ivan
author_sort Kim, HaEun
title MTOR modulation induces selective perturbations in histone methylation which influence the anti-proliferative effects of mTOR inhibitors
title_short MTOR modulation induces selective perturbations in histone methylation which influence the anti-proliferative effects of mTOR inhibitors
title_full MTOR modulation induces selective perturbations in histone methylation which influence the anti-proliferative effects of mTOR inhibitors
title_fullStr MTOR modulation induces selective perturbations in histone methylation which influence the anti-proliferative effects of mTOR inhibitors
title_full_unstemmed MTOR modulation induces selective perturbations in histone methylation which influence the anti-proliferative effects of mTOR inhibitors
title_sort mtor modulation induces selective perturbations in histone methylation which influence the anti-proliferative effects of mtor inhibitors
publishDate 2024
url https://hdl.handle.net/10356/178388
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