期刊
SCIENCE ADVANCES
卷 7, 期 29, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abg7444
关键词
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资金
- New York University Grossman School of Medicine
- National Cancer Institute [P30CA016087]
- National Institutes of Health (NIH) [R01CA199652]
- Howard Hughes Medical Institute (HHMI)
- Making Headway Foundation St. Baldrick's Research Grant [189290]
- American Cancer Society [DMC-PF-17-035-01]
- Hyundai Hope on Wheels Research Grant
- Alex's Lemonade Stand Foundation
- Simons Foundation
- NIH [K99AA024837]
- NYSTEM Stem Cell Biology training grant [C322560GG]
- NIH/NINDS [R01NS102665]
- NYSTEM (NY State Stem Cell Science) [IIRP C32595GG]
- NIH/NIBIB [R01EB028774]
- DFG (German Research Foundation)
The study identified that H3K36me2 promotes tumorigenesis in H3K27M-DIPG by affecting the writing activity of NSD1 and NSD2, as well as the reading factors LEDGF and HDGF2. Loss of NSD1/2 impedes cellular proliferation and tumorigenesis.
Histone H3K27M is a driving mutation in diffuse intrinsic pontine glioma (DIPG), a deadly pediatric brain tumor. H3K27M reshapes the epigenome through a global inhibition of PRC2 catalytic activity and displacement of H3K27me2/3, promoting oncogenesis of DIPG. As a consequence, a histone modification H3K36me2, antagonistic to H3K27me2/3, is aberrantly elevated. Here, we investigate the role of H3K36me2 in H3K27M-DIPG by tackling its upstream catalyzing enzymes (writers) and downstream binding factors (readers). We determine that NSD1 and NSD2 are the key writers for H3K36me2. Loss of NSD1/2 in H3K27M-DIPG impedes cellular proliferation and tumorigenesis by disrupting tumor-promoting transcriptional programs. Further, we demonstrate that LEDGF and HDGF2 are the main readers mediating the protumorigenic effects downstream of NSD1/2-H3K36me2. Treatment with a chemically modified peptide mimicking endogenous H3K36me2 dislodges LEDGF/HDGF2 from chromatin and specifically inhibits the proliferation of H3K27M-DIPG. Our results indicate a functional pathway of NSD1/2-H3K36me2-LEDGF/HDGF2 as an acquired dependency in H3K27M-DIPG.
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