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

by Selleckchem | Jul 30 2023

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.

Comments:

The information you provided describes a study conducted on small intestinal neuroendocrine tumors (SI-NETs) and their association with the enhancer of zeste homolog 2 (EZH2) histone methyltransferase. Here's a summary of the key findings:

1. Expression of EZH2: While enterochromaffin cells in the small intestine do not express EZH2, primary SI-NETs and their metastases showed high and differential expression of EZH2.

2. Effects of EZH2 silencing: In the SI-NET cell line CNDT2.5, silencing EZH2 reduced cell proliferation and induced apoptosis. This suggests that EZH2 plays a role in promoting tumor growth and inhibiting cell death.

3. EZH2 knockout in a mouse model: In a CNDT2.5 SI-NET xenograft mouse model, EZH2 knockout inhibited tumor progression. This further supports the idea that EZH2 is involved in tumor growth.

4. EZH2 inhibitors: Treatment of SI-NET cell lines CNDT2.5 and GOT1 with EZH2-specific inhibitors, such as CPI-1205 and GSK126, decreased cell viability, promoted apoptosis, and repressed proliferation. This indicates that targeting EZH2 with inhibitors may have therapeutic potential.

5. Metformin's effect on EZH2: Metformin, a drug commonly used to treat diabetes, suppressed EZH2 expression in CNDT2.5 and GOT1 cells. Additionally, metformin inhibited cell proliferation, suggesting it may have therapeutic benefits for SI-NETs.

6. Combined effects of EZH2 inhibitors and metformin: Treatment of three-dimensional cell spheroids derived from GOT1 cells with CPI-1205 or metformin arrested cell proliferation and decreased spheroid size. This indicates that the combination of EZH2 inhibitors and metformin may have synergistic effects in inhibiting tumor growth.

Based on these findings, the study suggests that EZH2 could be a potential oncogene in SI-NETs and that EZH2 inhibitors like CPI-1205 and EZH2 suppressors like metformin could be further explored as therapeutic options for patients with SI-NETs. However, it's important to note that further evaluation and clinical studies are needed to determine the efficacy and safety of these treatments in human patients.