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EHMT2 epigenetically suppresses Wnt signaling and is a potential target in embryonal rhabdomyosarcoma
- Source :
- eLife, eLife, Vol 9 (2020)
- Publication Year :
- 2020
- Publisher :
- eLife Sciences Publications, Ltd, 2020.
-
Abstract
- Wnt signaling is downregulated in embryonal rhabdomyosarcoma (ERMS) and contributes to the block of differentiation. Epigenetic mechanisms leading to its suppression are unknown and could pave the way toward novel therapeutic modalities. We demonstrate that EHMT2 suppresses canonical Wnt signaling by activating expression of the Wnt antagonist DKK1. Inhibition of EHMT2 expression or activity in human ERMS cell lines reduced DKK1 expression and elevated canonical Wnt signaling resulting in myogenic differentiation in vitro and in mouse xenograft models in vivo. Mechanistically, EHMT2 impacted Sp1 and p300 enrichment at the DKK1 promoter. The reduced tumor growth upon EHMT2 deficiency was reversed by recombinant DKK1 or LGK974, which also inhibits Wnt signaling. Consistently, among 13 drugs targeting chromatin modifiers, EHMT2 inhibitors were highly effective in reducing ERMS cell viability. Our study demonstrates that ERMS cells are vulnerable to EHMT2 inhibitors and suggest that targeting the EHMT2-DKK1-β-catenin node holds promise for differentiation therapy.
- Subjects :
- 0301 basic medicine
Mouse
Pyridines
Epigenesis, Genetic
Mice
0302 clinical medicine
Differentiation therapy
Histocompatibility Antigens
Rhabdomyosarcoma, Embryonal
Biology (General)
Wnt Signaling Pathway
General Neuroscience
Wnt signaling pathway
Gene Expression Regulation, Developmental
Cell Differentiation
General Medicine
Chromosomes and Gene Expression
Chromatin
Gene Expression Regulation, Neoplastic
030220 oncology & carcinogenesis
Pyrazines
Medicine
Puromycin
RNA Interference
Research Article
musculoskeletal diseases
QH301-705.5
Science
Mice, Nude
Biology
General Biochemistry, Genetics and Molecular Biology
EHMT2
03 medical and health sciences
Cell Line, Tumor
medicine
cancer
Animals
Humans
Dimethyl Sulfoxide
Genetic Predisposition to Disease
Viability assay
Epigenetics
Cell Proliferation
General Immunology and Microbiology
epigenetics
Histone-Lysine N-Methyltransferase
medicine.disease
030104 developmental biology
DKK1
Cancer research
Quinazolines
Embryonal rhabdomyosarcoma
methylation
Subjects
Details
- Language :
- English
- ISSN :
- 2050084X
- Volume :
- 9
- Database :
- OpenAIRE
- Journal :
- eLife
- Accession number :
- edsair.doi.dedup.....55d196768f4fe347a265e21324806f95