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 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.

• Authors: Elham Barazeghi, Per Hellman, Olov Norlén, Gunnar Westin, Peter Stålberg
• Journal: Scientific reports (Sci Rep) Vol. 11 Issue 1 Pg. 22733 (11 23 2021) ISSN: 2045-2322 [Electronic] England
• PMID: 34815475 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s).

Chemical References

• Biomarkers, Tumor
• Enzyme Inhibitors
• Hypoglycemic Agents
• Indoles
• Piperidines
• (R)-N-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)-1H-indole-3-carboxamide
• Metformin
• EZH2 protein, human
• Enhancer of Zeste Homolog 2 Protein

Topics

• Animals
• Apoptosis
• Biomarkers, Tumor (genetics, metabolism)
• Cell Movement
• Cell Proliferation
• Drug Therapy, Combination
• Enhancer of Zeste Homolog 2 Protein (antagonists & inhibitors)
• Enzyme Inhibitors (pharmacology)
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Hypoglycemic Agents (pharmacology)
• Indoles (pharmacology)
• Intestinal Neoplasms (drug therapy, metabolism, pathology)
• Intestine, Small (drug effects, pathology)
• Metformin (pharmacology)
• Mice
• Mice, Nude
• Neuroendocrine Tumors (drug therapy, metabolism, pathology)
• Piperidines (pharmacology)
• Prognosis
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays