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EHMT2 epigenetically suppresses Wnt signaling and is a potential target in embryonal rhabdomyosarcoma
Ananya Pal1, Jia Yu Leung1,2, Gareth Chin Khye Ang1,2
1Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
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.
Insights
EHMT2 inhibition reactivates Wnt signaling by reducing DKK1, promoting differentiation in embryonal rhabdomyosarcoma (ERMS). EHMT2 inhibitors show therapeutic promise for ERMS differentiation therapy.
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- Wnt signaling is crucial for development but is downregulated in embryonal rhabdomyosarcoma (ERMS), hindering cell differentiation.
- The epigenetic mechanisms responsible for Wnt signaling suppression in ERMS remain largely unknown.
- Understanding these mechanisms could reveal new therapeutic strategies for ERMS.
Purpose of the Study:
- To investigate the epigenetic regulation of Wnt signaling in ERMS.
- To identify potential therapeutic targets for ERMS differentiation therapy.
Main Methods:
- Utilized human ERMS cell lines and mouse xenograft models.
- Investigated the role of EHMT2 (euchromatic histone-modifying enzyme 2) in regulating Wnt signaling.
- Analyzed gene expression, protein enrichment at the DKK1 promoter, and tumor growth.
- Tested the efficacy of EHMT2 inhibitors and Wnt signaling modulators.
Main Results:
- EHMT2 was found to suppress canonical Wnt signaling by increasing the expression of the Wnt antagonist DKK1.
- Inhibition of EHMT2 in ERMS cells led to decreased DKK1 expression, enhanced Wnt signaling, and induced myogenic differentiation in vitro and in vivo.
- EHMT2's mechanism involves influencing Sp1 and p300 enrichment at the DKK1 promoter.
- EHMT2 inhibitors were effective in reducing ERMS cell viability, and targeting the EHMT2-DKK1-β-catenin pathway showed therapeutic potential.
Conclusions:
- ERMS cells are sensitive to EHMT2 inhibition, suggesting a therapeutic vulnerability.
- Targeting the EHMT2-DKK1-β-catenin signaling axis offers a promising strategy for differentiation therapy in ERMS.
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