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H3K9 dimethylation safeguards cancer cells against activation of the interferon pathway

Activation of interferon genes constitutes an important anticancer pathway able to restrict proliferation of cancer cells. Here, we demonstrate that the H3K9me3 histone methyltransferase (HMT) suppressor of variegation 3–9 homolog 1 (SUV39H1) is required for the proliferation of acute myeloid leukem...

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Autores principales: Hansen, Anne Meldgaard, Ge, Ying, Schuster, Mikkel Bruhn, Pundhir, Sachin, Jakobsen, Janus Schou, Kalvisa, Adrija, Tapia, Marta Cecylia, Gordon, Sandra, Ambri, Francesca, Bagger, Frederik Otzen, Pandey, Deo, Helin, Kristian, Porse, Bo Torben
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8932663/
https://www.ncbi.nlm.nih.gov/pubmed/35302840
http://dx.doi.org/10.1126/sciadv.abf8627
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author Hansen, Anne Meldgaard
Ge, Ying
Schuster, Mikkel Bruhn
Pundhir, Sachin
Jakobsen, Janus Schou
Kalvisa, Adrija
Tapia, Marta Cecylia
Gordon, Sandra
Ambri, Francesca
Bagger, Frederik Otzen
Pandey, Deo
Helin, Kristian
Porse, Bo Torben
author_facet Hansen, Anne Meldgaard
Ge, Ying
Schuster, Mikkel Bruhn
Pundhir, Sachin
Jakobsen, Janus Schou
Kalvisa, Adrija
Tapia, Marta Cecylia
Gordon, Sandra
Ambri, Francesca
Bagger, Frederik Otzen
Pandey, Deo
Helin, Kristian
Porse, Bo Torben
author_sort Hansen, Anne Meldgaard
collection PubMed
description Activation of interferon genes constitutes an important anticancer pathway able to restrict proliferation of cancer cells. Here, we demonstrate that the H3K9me3 histone methyltransferase (HMT) suppressor of variegation 3–9 homolog 1 (SUV39H1) is required for the proliferation of acute myeloid leukemia (AML) and find that its loss leads to activation of the interferon pathway. Mechanistically, we show that this occurs via destabilization of a complex composed of SUV39H1 and the two H3K9me2 HMTs, G9A and GLP. Indeed, loss of H3K9me2 correlated with the activation of key interferon pathway genes, and interference with the activities of G9A/GLP largely phenocopied loss of SUV39H1. Last, we demonstrate that inhibition of G9A/GLP synergized with DNA demethylating agents and that SUV39H1 constitutes a potential biomarker for the response to hypomethylation treatment. Collectively, we uncovered a clinically relevant role for H3K9me2 in safeguarding cancer cells against activation of the interferon pathway.
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spelling pubmed-89326632022-03-31 H3K9 dimethylation safeguards cancer cells against activation of the interferon pathway Hansen, Anne Meldgaard Ge, Ying Schuster, Mikkel Bruhn Pundhir, Sachin Jakobsen, Janus Schou Kalvisa, Adrija Tapia, Marta Cecylia Gordon, Sandra Ambri, Francesca Bagger, Frederik Otzen Pandey, Deo Helin, Kristian Porse, Bo Torben Sci Adv Biomedicine and Life Sciences Activation of interferon genes constitutes an important anticancer pathway able to restrict proliferation of cancer cells. Here, we demonstrate that the H3K9me3 histone methyltransferase (HMT) suppressor of variegation 3–9 homolog 1 (SUV39H1) is required for the proliferation of acute myeloid leukemia (AML) and find that its loss leads to activation of the interferon pathway. Mechanistically, we show that this occurs via destabilization of a complex composed of SUV39H1 and the two H3K9me2 HMTs, G9A and GLP. Indeed, loss of H3K9me2 correlated with the activation of key interferon pathway genes, and interference with the activities of G9A/GLP largely phenocopied loss of SUV39H1. Last, we demonstrate that inhibition of G9A/GLP synergized with DNA demethylating agents and that SUV39H1 constitutes a potential biomarker for the response to hypomethylation treatment. Collectively, we uncovered a clinically relevant role for H3K9me2 in safeguarding cancer cells against activation of the interferon pathway. American Association for the Advancement of Science 2022-03-18 /pmc/articles/PMC8932663/ /pubmed/35302840 http://dx.doi.org/10.1126/sciadv.abf8627 Text en Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). https://creativecommons.org/licenses/by-nc/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (https://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.
spellingShingle Biomedicine and Life Sciences
Hansen, Anne Meldgaard
Ge, Ying
Schuster, Mikkel Bruhn
Pundhir, Sachin
Jakobsen, Janus Schou
Kalvisa, Adrija
Tapia, Marta Cecylia
Gordon, Sandra
Ambri, Francesca
Bagger, Frederik Otzen
Pandey, Deo
Helin, Kristian
Porse, Bo Torben
H3K9 dimethylation safeguards cancer cells against activation of the interferon pathway
title H3K9 dimethylation safeguards cancer cells against activation of the interferon pathway
title_full H3K9 dimethylation safeguards cancer cells against activation of the interferon pathway
title_fullStr H3K9 dimethylation safeguards cancer cells against activation of the interferon pathway
title_full_unstemmed H3K9 dimethylation safeguards cancer cells against activation of the interferon pathway
title_short H3K9 dimethylation safeguards cancer cells against activation of the interferon pathway
title_sort h3k9 dimethylation safeguards cancer cells against activation of the interferon pathway
topic Biomedicine and Life Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8932663/
https://www.ncbi.nlm.nih.gov/pubmed/35302840
http://dx.doi.org/10.1126/sciadv.abf8627
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