KDM5B promotes tumorigenesis of Ewing sarcoma via FBXW7/CCNE1 axis

Area of Science:

• Oncology
• Epigenetics
• Molecular Biology

Background:

• Ewing sarcoma (EwS) is an aggressive pediatric cancer with limited treatment options for relapsed/refractory disease.
• Targeting driver fusion oncoproteins in EwS is challenging, highlighting the need for alternative therapeutic strategies.
• Epigenetic mechanisms are increasingly recognized as crucial in EwS development and potential therapeutic targets.

Purpose of the Study:

• To investigate the role of lysine demethylase 5B (KDM5B) in Ewing sarcoma.
• To explore KDM5B as a potential therapeutic target for EwS treatment.

Main Methods:

• Assessed KDM5B expression in EwS tissues and correlated it with patient outcomes.
• Utilized KDM5B knockdown and a specific inhibitor (AS-8351) in EwS cell lines.
• Performed bioinformatics analysis to identify KDM5B-regulated pathways.
• Investigated the molecular mechanism of KDM5B action on CCNE1 and FBXW7.
• Evaluated the efficacy of AS-8351 in a xenograft mouse model.

Main Results:

• KDM5B was upregulated in EwS and associated with poor patient prognosis.
• KDM5B inhibition suppressed EwS cell proliferation and induced cell cycle arrest.
• KDM5B overexpression increased CCNE1 protein levels by downregulating FBXW7 expression via H3K4me3 demethylation at the FBXW7 promoter.
• AS-8351 demonstrated antitumor effects in vivo, inhibiting tumor growth in mice.

Conclusions:

• KDM5B drives EwS proliferation by attenuating FBXW7 transcription and accumulating CCNE1 protein.
• Targeting KDM5B with epigenetic drugs represents a promising therapeutic strategy for Ewing sarcoma.