EHMT2 epigenetically suppresses Wnt signaling and is a potential target in embryonal rhabdomyosarcoma
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 b...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2020-11-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/57683 |
| _version_ | 1811253156482383872 |
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| author | Ananya Pal Jia Yu Leung Gareth Chin Khye Ang Vinay Kumar Rao Luca Pignata Huey Jin Lim Maxime Hebrard Kenneth TE Chang Victor KM Lee Ernesto Guccione Reshma Taneja |
| author_facet | Ananya Pal Jia Yu Leung Gareth Chin Khye Ang Vinay Kumar Rao Luca Pignata Huey Jin Lim Maxime Hebrard Kenneth TE Chang Victor KM Lee Ernesto Guccione Reshma Taneja |
| author_sort | Ananya Pal |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T16:46:31Z |
| format | Article |
| id | doaj.art-db70951a46d04ec4b8dcef9cb836464b |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T16:46:31Z |
| publishDate | 2020-11-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-db70951a46d04ec4b8dcef9cb836464b2022-12-22T03:24:35ZengeLife Sciences Publications LtdeLife2050-084X2020-11-01910.7554/eLife.57683EHMT2 epigenetically suppresses Wnt signaling and is a potential target in embryonal rhabdomyosarcomaAnanya Pal0Jia Yu Leung1https://orcid.org/0000-0003-1317-8396Gareth Chin Khye Ang2Vinay Kumar Rao3Luca Pignata4Huey Jin Lim5Maxime Hebrard6Kenneth TE Chang7https://orcid.org/0000-0001-5244-4285Victor KM Lee8Ernesto Guccione9Reshma Taneja10https://orcid.org/0000-0001-6214-6177Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, SingaporeDepartment of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, SingaporeDepartment of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, SingaporeDepartment of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, SingaporeInstitute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, SingaporeDepartment of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, SingaporeInstitute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, SingaporeDepartment of Pathology, KK Women and Children’s Hospital, Singapore, SingaporeDepartment of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, SingaporeInstitute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, SingaporeDepartment of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, SingaporeWnt 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.https://elifesciences.org/articles/57683epigeneticsmethylationcancer |
| spellingShingle | Ananya Pal Jia Yu Leung Gareth Chin Khye Ang Vinay Kumar Rao Luca Pignata Huey Jin Lim Maxime Hebrard Kenneth TE Chang Victor KM Lee Ernesto Guccione Reshma Taneja EHMT2 epigenetically suppresses Wnt signaling and is a potential target in embryonal rhabdomyosarcoma eLife epigenetics methylation cancer |
| title | EHMT2 epigenetically suppresses Wnt signaling and is a potential target in embryonal rhabdomyosarcoma |
| title_full | EHMT2 epigenetically suppresses Wnt signaling and is a potential target in embryonal rhabdomyosarcoma |
| title_fullStr | EHMT2 epigenetically suppresses Wnt signaling and is a potential target in embryonal rhabdomyosarcoma |
| title_full_unstemmed | EHMT2 epigenetically suppresses Wnt signaling and is a potential target in embryonal rhabdomyosarcoma |
| title_short | EHMT2 epigenetically suppresses Wnt signaling and is a potential target in embryonal rhabdomyosarcoma |
| title_sort | ehmt2 epigenetically suppresses wnt signaling and is a potential target in embryonal rhabdomyosarcoma |
| topic | epigenetics methylation cancer |
| url | https://elifesciences.org/articles/57683 |
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