EZH2 presents a therapeutic target for neuroendocrine tumors of the small intestine
Abstract Small intestinal neuroendocrine tumors (SI-NETs) are slow-growing tumors that seem genetically quite stable without highly recurrent mutations, but are epigenetically dysregulated. In contrast to the undetectable expression of the enhancer of zeste homolog 2 (EZH2) histone methyltransferase...
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2021
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oai:doaj.org-article:d351b9e2cae3458c9b1d12c37c08e7b82021-11-28T12:20:05ZEZH2 presents a therapeutic target for neuroendocrine tumors of the small intestine10.1038/s41598-021-02181-72045-2322https://doaj.org/article/d351b9e2cae3458c9b1d12c37c08e7b82021-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-02181-7https://doaj.org/toc/2045-2322Abstract Small intestinal neuroendocrine tumors (SI-NETs) are slow-growing tumors that seem genetically quite stable without highly recurrent mutations, but are epigenetically dysregulated. In contrast to the undetectable expression of the enhancer of zeste homolog 2 (EZH2) histone methyltransferase in the enterochromaffin cells of the small intestine, we found high and differential expression of EZH2 in primary SI-NETs and corresponding metastases. Silencing EZH2 in the SI-NET cell line CNDT2.5 reduced cell proliferation and induced apoptosis. Furthermore, EZH2 knockout inhibited tumor progression in a CNDT2.5 SI-NET xenograft mouse model, and treatment of SI-NET cell lines CNDT2.5 and GOT1 with the EZH2-specific inhibitor CPI-1205 decreased cell viability and promoted apoptosis. Moreover, CPI-1205 treatment reduced migration capacity of CNDT2.5 cells. The EZH2 inhibitor GSK126 also repressed proliferation of CNDT2.5 cells. Recently, metformin has received wide attention as a therapeutic option in diverse cancers. In CNDT2.5 and GOT1 cells, metformin suppressed EZH2 expression, and inhibited cell proliferation. Exposure of GOT1 three-dimensional cell spheroids to CPI-1205 or metformin arrested cell proliferation and decreased spheroid size. These novel findings support a possible role of EZH2 as a candidate oncogene in SI-NETs, and suggest that CPI-1205 and metformin should be further evaluated as therapeutic options for patients with SI-NETs.Elham BarazeghiPer HellmanOlov NorlénGunnar WestinPeter StålbergNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021) |
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Medicine R Science Q Elham Barazeghi Per Hellman Olov Norlén Gunnar Westin Peter Stålberg EZH2 presents a therapeutic target for neuroendocrine tumors of the small intestine |
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Abstract Small intestinal neuroendocrine tumors (SI-NETs) are slow-growing tumors that seem genetically quite stable without highly recurrent mutations, but are epigenetically dysregulated. In contrast to the undetectable expression of the enhancer of zeste homolog 2 (EZH2) histone methyltransferase in the enterochromaffin cells of the small intestine, we found high and differential expression of EZH2 in primary SI-NETs and corresponding metastases. Silencing EZH2 in the SI-NET cell line CNDT2.5 reduced cell proliferation and induced apoptosis. Furthermore, EZH2 knockout inhibited tumor progression in a CNDT2.5 SI-NET xenograft mouse model, and treatment of SI-NET cell lines CNDT2.5 and GOT1 with the EZH2-specific inhibitor CPI-1205 decreased cell viability and promoted apoptosis. Moreover, CPI-1205 treatment reduced migration capacity of CNDT2.5 cells. The EZH2 inhibitor GSK126 also repressed proliferation of CNDT2.5 cells. Recently, metformin has received wide attention as a therapeutic option in diverse cancers. In CNDT2.5 and GOT1 cells, metformin suppressed EZH2 expression, and inhibited cell proliferation. Exposure of GOT1 three-dimensional cell spheroids to CPI-1205 or metformin arrested cell proliferation and decreased spheroid size. These novel findings support a possible role of EZH2 as a candidate oncogene in SI-NETs, and suggest that CPI-1205 and metformin should be further evaluated as therapeutic options for patients with SI-NETs. |
format |
article |
author |
Elham Barazeghi Per Hellman Olov Norlén Gunnar Westin Peter Stålberg |
author_facet |
Elham Barazeghi Per Hellman Olov Norlén Gunnar Westin Peter Stålberg |
author_sort |
Elham Barazeghi |
title |
EZH2 presents a therapeutic target for neuroendocrine tumors of the small intestine |
title_short |
EZH2 presents a therapeutic target for neuroendocrine tumors of the small intestine |
title_full |
EZH2 presents a therapeutic target for neuroendocrine tumors of the small intestine |
title_fullStr |
EZH2 presents a therapeutic target for neuroendocrine tumors of the small intestine |
title_full_unstemmed |
EZH2 presents a therapeutic target for neuroendocrine tumors of the small intestine |
title_sort |
ezh2 presents a therapeutic target for neuroendocrine tumors of the small intestine |
publisher |
Nature Portfolio |
publishDate |
2021 |
url |
https://doaj.org/article/d351b9e2cae3458c9b1d12c37c08e7b8 |
work_keys_str_mv |
AT elhambarazeghi ezh2presentsatherapeutictargetforneuroendocrinetumorsofthesmallintestine AT perhellman ezh2presentsatherapeutictargetforneuroendocrinetumorsofthesmallintestine AT olovnorlen ezh2presentsatherapeutictargetforneuroendocrinetumorsofthesmallintestine AT gunnarwestin ezh2presentsatherapeutictargetforneuroendocrinetumorsofthesmallintestine AT peterstalberg ezh2presentsatherapeutictargetforneuroendocrinetumorsofthesmallintestine |
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1718408046033502208 |