EZH2 inhibition induces pyroptosis via RHA-mediated S100A9 overexpression in myelodysplastic syndromes

EZH2 inhibition induces pyroptosis via RHA-mediated S100A9 overexpression in myelodysplastic syndromes

Abstract Myelodysplastic Syndromes (MDS) represent a group of heterogeneous myeloid clonal diseases derived from aberrant hematopoietic stem/progenitor cells. Enhancer of zeste homolog 2 (EZH2) is an important regulator in gene expression through methyltransferase-dependent or methyltransferase-inde...

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Main Authors: Qi Zhang, Yingwan Luo, Li Ye, Yuxia Wang, Lu Wang, Wenli Yang, Wei Lang, Shuanghong Zhu, Lingxu Jiang, Weimei Jin, Chen Mei, Xinping Zhou, Yanling Ren, Liya Ma, Gaixiang Xu, Bowatte Gedara Lakmal Vimukthi Bandara Bowattage, Hongyan Tong, Jie Sun
Format: Article
Language:English
Published: BMC 2025-01-01
Series:Experimental Hematology & Oncology
Subjects:
Myelodysplastic syndromes
Enhancer of zeste homologue 2
RNA helicase A
S100 calcium binding protein A9
Pyroptosis
Online Access:https://doi.org/10.1186/s40164-025-00600-3
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Summary:Abstract Myelodysplastic Syndromes (MDS) represent a group of heterogeneous myeloid clonal diseases derived from aberrant hematopoietic stem/progenitor cells. Enhancer of zeste homolog 2 (EZH2) is an important regulator in gene expression through methyltransferase-dependent or methyltransferase-independent mechanisms. Herein, we found EZH2 inhibition led to MDS cell pyroptosis through RNA Helicase A (RHA) down-regulation induced overexpression of S100A9, a key regulator of inflammasome activation and pyroptosis. Moreover, EZH2 inhibitor reduced tumor burden and prolonged the survival of the mice transplanted with MDS cells. In summary, our results uncovered a novel pyroptosis pathway induced by EZH2 inhibition and provided a rationale for EZH2 inhibitor treatment in MDS.
ISSN:2162-3619

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