The PRC2 molecule EED is a target of epigenetic therapy for neuroblastoma

• Published in: European journal of cell biology Vol. 101; no. 3; p. 151238
• Main Authors: Shaliman, Dilibaerguli, Takenobu, Hisanori, Sugino, Ryuichi P., Ohira, Miki, Kamijo, Takehiko
• Format: Journal Article
• Language: English
• Published: Germany Elsevier GmbH 01.06.2022; Elsevier
• Subjects: Cell Proliferation - genetics; EED; Epigenesis, Genetic; Histone code; Humans; N-Myc Proto-Oncogene Protein - genetics; N-Myc Proto-Oncogene Protein - metabolism; Neuroblastoma; Neuroblastoma - drug therapy; Neuroblastoma - genetics; Neuroblastoma - metabolism; Polycomb; Polycomb Repressive Complex 2 - genetics; Polycomb Repressive Complex 2 - metabolism; Polycomb; Neuroblastoma; EED; Histone code
• ISSN: 0171-9335; 1618-1298
• DOI: 10.1016/j.ejcb.2022.151238

Epigenetic modifications by polycomb repressive complex (PRC) molecules appear to play a role in the tumorigenesis and aggressiveness of neuroblastoma (NB). Embryonic ectoderm development (EED) is a member of the PRC2 complex that binds to the H3K27me3 mark deposited by EZH2 via propagation on adjacent nucleosomes. We herein investigated the molecular roles of EED in MYCN-amplified NB cells using EED-knockdown (KD) shRNAs, EED-knockout sgRNAs, and the EED small molecule inhibitor EED226. The suppression of EED markedly inhibited NB cell proliferation and flat and soft agar colony formation. A transcriptome analysis using microarrays of EED-KD NB cells indicated the de-repression of cell cycle-regulated and differentiation-related genes. The results of a GSEA analysis suggested that inhibitory cell cycle-regulated gene sets were markedly up-regulated. Furthermore, an epigenetic treatment with the EED inhibitor EED226 and the HDAC inhibitors valproic acid/SAHA effectively suppressed NB cell proliferation and colony formation. This combined epigenetic treatment up-regulated cell cycle-regulated and differentiation-related genes. The ChIP sequencing analysis of histone codes and PRC molecules suggested an epigenetic background for the de-repression of down-regulated genes in MYCN-amplified/PRC2 up-regulated NB. •Suppression of EED markedly inhibited NB cell proliferation/colony formation.•EED repressed differentiation-related and cell cycle arrest/death control genes as an important molecule of PRC2 complex.•EED inhibition and HDAC inhibitor effectively suppressed NB cell proliferation.