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EZH2 inhibition induces senescence via ERK1/2 signaling pathway in multiple myeloma
Shushan Guo1,2,3, Qiongwei Tang2, Xuejie Gao2
1Shanghai Clinical College, Anhui Medical University, Shanghai 200072, China.
Abstract:
Epigenetic modifications play an important role in cellular senescence, and enhancer of zeste homolog 2 (EZH2) is a key methyltransferase involved in epigenetic remodeling in multiple myeloma (MM) cells. We have previously demonstrated that GSK126, a specific EZH2 inhibitor, exhibits anti-MM therapeutic efficacy and safety in vivo and in vitro; however, its specific mechanism remains unclear. This study shows that GSK126 induces cellular senescence in MM, which is characterized by the accumulation of senescence-associated heterochromatin foci (SAHF) and p21, and increased senescence-associated β galactosidase activity. Furthermore, EZH2 is inhibited in ribonucleotide reductase regulatory subunit M2 (RRM2)-overexpressing OCI-MY5 and RPMI-8226 cells. RRM2 overexpression inhibits the methyltransferase function of EZH2 and promotes its degradation through the ubiquitin-proteasome pathway, thereby inducing cellular senescence. In this senescence model, Lamin B1, a key component of the nuclear envelope and a marker of senescence, does not decrease but instead undergoes aberrant accumulation. Meanwhile, phosphorylation of extracellular signal-regulated protein kinase (ERK1/2) is significantly increased. The inhibition of ERK1/2 phosphorylation in turn partially restores Lamin B1 level and alleviates senescence. These findings suggest that EZH2 inhibition increases Lamin B1 level and induces senescence by promoting ERK1/2 phosphorylation. These data indicate that EZH2 plays an important role in MM cellular senescence and provide insights into the relationships among Lamin B1, p-ERK1/2, and cellular senescence.
Insights
Enhancer of zeste homolog 2 (EZH2) inhibition triggers cellular senescence in multiple myeloma (MM) by increasing Lamin B1 and promoting ERK1/2 phosphorylation. This reveals a novel mechanism for MM senescence induction.
Area of Science:
- Oncology
- Epigenetics
- Cellular Biology
Background:
- Epigenetic modifications, particularly by enhancer of zeste homolog 2 (EZH2), are crucial in multiple myeloma (MM) cellular senescence.
- Previous studies showed GSK126, an EZH2 inhibitor, has therapeutic potential in MM, but its mechanism was unclear.
Purpose of the Study:
- To elucidate the specific mechanism by which EZH2 inhibition induces cellular senescence in multiple myeloma.
- To investigate the roles of Lamin B1 and extracellular signal-regulated protein kinase (ERK1/2) in EZH2-mediated MM senescence.
Main Methods:
- Utilized GSK126, a specific EZH2 inhibitor, in multiple myeloma cell lines (OCI-MY5, RPMI-8226).
- Assessed cellular senescence markers including senescence-associated heterochromatin foci (SAHF), p21, and senescence-associated β-galactosidase activity.
- Investigated the impact of ribonucleotide reductase regulatory subunit M2 (RRM2) overexpression on EZH2 function and degradation.
- Analyzed Lamin B1 levels and ERK1/2 phosphorylation in response to EZH2 inhibition and RRM2 overexpression.
- Examined the effect of ERK1/2 phosphorylation inhibition on Lamin B1 levels and senescence.
Main Results:
- GSK126 treatment induced cellular senescence in MM cells, marked by SAHF, p21 accumulation, and increased β-galactosidase activity.
- RRM2 overexpression inhibited EZH2 methyltransferase activity and promoted its degradation, leading to senescence.
- Contrary to typical senescence markers, Lamin B1 levels increased, and ERK1/2 phosphorylation was elevated.
- Inhibiting ERK1/2 phosphorylation partially restored Lamin B1 levels and reduced senescence.
Conclusions:
- EZH2 inhibition induces cellular senescence in MM by increasing Lamin B1 levels and promoting ERK1/2 phosphorylation.
- RRM2 overexpression contributes to MM senescence by inhibiting EZH2 activity and promoting its degradation.
- This study uncovers a novel pathway involving EZH2, Lamin B1, and p-ERK1/2 in MM cellular senescence, offering potential therapeutic insights.
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