EZH2 presents a therapeutic target for neuroendocrine tumors of the small intestine

Sci Rep. 2021 Nov 23;11(1):22733. doi: 10.1038/s41598-021-02181-7.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / 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*
  • Intestinal Neoplasms / metabolism
  • Intestinal Neoplasms / pathology
  • Intestine, Small / drug effects*
  • Intestine, Small / pathology
  • Metformin / pharmacology
  • Mice
  • Mice, Nude
  • Neuroendocrine Tumors / drug therapy*
  • Neuroendocrine Tumors / metabolism
  • Neuroendocrine Tumors / pathology
  • Piperidines / pharmacology*
  • Prognosis
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • 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