H3K9 dimethylation safeguards cancer cells against activation of the interferon pathway

被引：21

作者：

Hansen, Anne Meldgaard ^{[1
,2
,3
]}

Ge, Ying ^{[1
,2
,3
]}

Schuster, Mikkel Bruhn ^{[1
,2
,3
]}

Pundhir, Sachin ^{[1
,2
,3
]}

Jakobsen, Janus Schou ^{[1
,2
,3
]}

Kalvisa, Adrija ^{[1
,2
,3
]}

Tapia, Marta Cecylia ^{[1
,2
,3
]}

Gordon, Sandra ^{[2
,3
]}

Ambri, Francesca ^{[2
,3
]}

Bagger, Frederik Otzen ^{[1
,2
,3
,4
]}

Pandey, Deo ^{[2
,5
]}

Helin, Kristian ^{[2
,3
,6
,7
,8
]}

Porse, Bo Torben ^{[1
,2
,3
]}

机构：

[1] Univ Copenhagen, Rigshosp, Fac Hlth Sci, Finsen Lab, DK-2200 Copenhagen, Denmark

[2] Univ Copenhagen, Biotech Res & Innovat Ctr BRIC, DK-2200 Copenhagen, Denmark

[3] Univ Copenhagen, Novo Nordisk Fdn Ctr Stem Cell Biol, Fac Hlth Sci, DanStem, DK-2200 Copenhagen, Denmark

[4] Copenhagen Univ Hosp, Ctr Genom Med, Copenhagen, Denmark

[5] Oslo Univ Hosp, Dept Microbiol, NO-0373 Oslo, Norway

[6] Mem Sloan Kettering Ctr, Cell Biol Program, New York, NY 10065 USA

[7] Mem Sloan Kettering Ctr, Ctr Epigenet Res, New York, NY 10065 USA

[8] Inst Canc Res, London SW3 6JB, England

来源：

SCIENCE ADVANCES | 2022年 / 8卷 / 11期

关键词：

HISTONE METHYLTRANSFERASE SUV39H1; DNA METHYLATION; DEMETHYLATING AGENTS; G9A; MUTATIONS; HETEROCHROMATIN; IDENTIFICATION; TRANSCRIPTION; INTERACTS; PROTEINS;

D O I：

10.1126/sciadv.abf8627

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：17

共 62 条

[1] Mutations in epigenetic modifiers in the pathogenesis and therapy of acute myeloid leukemia [J].