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
en 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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Senescencia Celular
/
Sistema de Señalización de MAP Quinasas
/
Proteína Potenciadora del Homólogo Zeste 2
/
Mieloma Múltiple
Límite:
Humans
Idioma:
En
Revista:
Acta Biochim Biophys Sin (Shanghai)
Asunto de la revista:
BIOFISICA
/
BIOQUIMICA
Año:
2024
Tipo del documento:
Article
País de afiliación:
China