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Blocking EZH2 methylation transferase activity by GSK126 decreases stem cell-like myeloma cells
Delong Zeng1, Maoxing Liu1, Jingxuan Pan1
1Jinan University Institute of Tumor Pharmacology, College of Pharmacy, Jinan University, Guangzhou, China.
Abstract:
EZH2 is a critical epigenetic regulator that is deregulated in various types of cancers including multiple myeloma (MM). In the present study, we hypothesized that targeting EZH2 might induce apoptosis in myeloma cells including stem cell-like cells (CSCs). We investigated the effect of EZH2 inhibition on MM cells using a potent inhibitor (GSK126). The results showed that GSK126 effectively abrogated the methylated histone 3 (H3K27me3) level in MM.1S and LP1 cells, and inhibited the number of live cells and colony formation in soft agar of six MM cell lines. GSK126 induced massive apoptosis in MM.1S, LP1 and RPMI8226 cells. Progressive release of mitochondrial cytochrome c and AIF into the cytosol was detected in GSK126-treated MM cells. GSK126 treatment elicited caspase-3-dependent MCL-1 cleavage with accumulation of proapoptotic truncated MCL-1. These results suggested that GSK126 triggers the intrinsic mitochondrial apoptosis pathway. Enhanced apoptosis was observed in the combination of GSK126 with bortezomib. Using ALDH and side population (SP) assays to characterize CSCs, we found that GSK126 eliminated the stem-like myeloma cells by blocking the Wnt/β-catenin pathway. The in vivo anti-tumor effect of GSK126 was confirmed by using RPMI8226 cells in a xenograft mouse model. In conclusion, our findings suggest that EZH2 inactivation by GSK126 is effective in killing MM cells and CSCs as a single agent or in combination with bortezomib. Clinical trial of GSK126 in patients with MM may be warranted.
Insights
Targeting enhancer of zeste homolog 2 (EZH2) with GSK126 effectively kills multiple myeloma cells and stem-like cells by inducing apoptosis. This approach shows promise as a single agent or in combination therapy for multiple myeloma.
Area of Science:
- Epigenetics
- Cancer Biology
- Molecular Oncology
Background:
- Enhancer of zeste homolog 2 (EZH2) is a key epigenetic regulator frequently deregulated in multiple myeloma (MM).
- Dysregulation of EZH2 contributes to MM pathogenesis and the survival of cancer stem cells (CSCs).
Purpose of the Study:
- To investigate the therapeutic potential of inhibiting EZH2 using GSK126 in multiple myeloma cells, including CSCs.
- To elucidate the mechanisms underlying EZH2 inhibition-induced cell death and its effects on CSCs.
Main Methods:
- Utilized GSK126, a potent EZH2 inhibitor, across six multiple myeloma cell lines.
- Assessed apoptosis, cell viability, colony formation, and mitochondrial pathway activation.
- Employed ALDH and side population (SP) assays to characterize and target CSCs.
- Evaluated in vivo efficacy in a xenograft mouse model.
Main Results:
- GSK126 effectively reduced H3K27me3 levels and inhibited MM cell proliferation and colony formation.
- GSK126 induced significant apoptosis via the intrinsic mitochondrial pathway, involving cytochrome c and AIF release, and caspase-3-dependent MCL-1 cleavage.
- GSK126 demonstrated efficacy against CSCs by inhibiting the Wnt/β-catenin pathway.
- Combined GSK126 with bortezomib enhanced apoptosis.
- GSK126 exhibited in vivo anti-tumor activity in a xenograft model.
Conclusions:
- EZH2 inhibition with GSK126 is a viable strategy for eliminating multiple myeloma cells, including CSCs.
- GSK126 shows potential as a single agent or in combination with bortezomib for MM treatment.
- Further clinical investigation of GSK126 in MM patients is warranted.
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