Aberrant activation of TRIP13-EZH2 signaling axis promotes stemness and therapy resistance in multiple myeloma

Xu, Lixia; Wang, Yingcong; Wang, Guanli; Guo, Shushan; Yu, Dandan; Feng, Qilin; Hu, Ke; Chen, Gege; Li, Bo; Xu, Zhijian; Jia, Xiaoli; Lu, Yumeng; Zhang, Hui; Gao, Xuejie; Chang, Shuaikang; Wang, Huaping; Wu, Xiaosong; Song, Dongli; Yang, Guang; Zhu, Huabin; Zhou, Jinfeng; Zhan, Fenghuang; Zhu, Weiliang; Shi, Jumei

doi:10.1038/s41375-023-01925-w

Cited by 6 publications

(3 citation statements)

References 14 publications

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“…Targeting EZH2 has exhibited therapeutic effects in various haematological malignancies [19,52,53]. In our previous study, we demonstrated that GSK126, an EZH2 inhibitor, exhibited therapeutic efficacy and safety in MM xenograft mice [21], but its specific mechanism remains unclear. EZH2 depletion activates p21 and induces senescence in melanoma [29,30].…”

Section: Discussionmentioning

confidence: 99%

“…Our previous study demonstrated the therapeutic effect of GSK126 on MM both in vivo and in vitro [21]. In this study, we investigated the effects of an EZH2 inhibitor (GSK126) on senescence in OCI-MY5 and RPMI-8226 cells.…”

Section: The Ezh2-specific Methyltransferase Inhibitor Gsk126 Induces...mentioning

confidence: 99%

“…High expression of EZH2 is associated with poor outcome in hematologic malignancies (myeloma and chronic lymphocytic leukaemia). In a previous study, we demonstrated that GSK126, a specific EZH2 inhibitor, exhibits anti-MM therapeutic efficacy and safety in vivo and in vitro [21]; however, its specific mechanism remains unclear. EZH2 plays a critical role in normal B cell development, and its expression level influences differentiation decisions [22].…”

Section: Introductionmentioning

confidence: 98%

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EZH2 inhibition induces senescence via ERK1/2 signaling pathway in multiple myeloma

Guo,

Tang,

Gao

et al. 2024

ABBS

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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.

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