H3K9 dimethylation safeguards cancer cells against activation of the interferon pathway

Anne Meldgaard Hansen, Ying Ge, Mikkel Bruhn Schuster, Sachin Pundhir, Janus Schou Jakobsen, Adrija Kalvisa, Marta Cecylia Tapia, Sandra Gordon, Francesca Ambri, Frederik Otzen Bagger, Deo Pandey, Kristian Helin, Bo Torben Porse

Abstract

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.

OriginalsprogEngelsk
Artikelnummerabf8627
TidsskriftScience Advances
Vol/bind8
Udgave nummer11
Sider (fra-til)eabf8627
DOI
StatusUdgivet - 18 mar. 2022

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