EZH2 inhibition induces senescence via ERK1/2 signaling pathway in multiple myeloma.
Acta Biochim Biophys Sin (Shanghai)
; 56(7): 1055-1064, 2024 May 27.
Article
in En
| MEDLINE
| ID: mdl-38804044
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 ß 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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Cellular Senescence
/
MAP Kinase Signaling System
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Enhancer of Zeste Homolog 2 Protein
/
Multiple Myeloma
Limits:
Humans
Language:
En
Journal:
Acta Biochim Biophys Sin (Shanghai)
Journal subject:
BIOFISICA
/
BIOQUIMICA
Year:
2024
Document type:
Article
Affiliation country:
Country of publication: