RRC ID 78726
Author Akita N, Okada R, Mukae K, Sugino RP, Takenobu H, Chikaraishi K, Ochiai H, Yamaguchi Y, Ohira M, Koseki H, Kamijo T.
Title Polycomb group protein BMI1 protects neuroblastoma cells against DNA damage-induced apoptotic cell death.
Journal Exp Cell Res
Abstract The overexpression of BMI1, a polycomb protein, correlates with cancer development and aggressiveness. We previously reported that MYCN-induced BMI1 positively regulated neuroblastoma (NB) cell proliferation via the transcriptional inhibition of tumor suppressors in NB cells. To assess the potential of BMI1 as a new target for NB therapy, we examined the effects of reductions in BMI1 on NB cells. BMI1 knockdown (KD) in NB cells significantly induced their differentiation for up to 7 days. BMI1 depletion significantly induced apoptotic NB cell death for up to 14 days along with the activation of p53, increases in p73, and induction of p53 family downstream molecules and pathways, even in p53 mutant cells. BMI1 depletion in vivo markedly suppressed NB xenograft tumor growth. BMI1 reductions activated ATM and increased γ-H2AX in NB cells. These DNA damage signals and apoptotic cell death were not canceled by the transduction of the polycomb group molecules EZH2 and RING1B. Furthermore, EZH2 and RING1B KD did not induce apoptotic NB cell death to the same extent as BMI1 KD. Collectively, these results suggest the potential of BMI1 as a target of molecular therapy for NB and confirmed, for the first time, the shared role of PcG proteins in the DNA damage response of NB cells.
Volume 422(1)
Pages 113412
Published 2023-1-1
DOI 10.1016/j.yexcr.2022.113412
PII S0014-4827(22)00405-0
PMID 36370852
MeSH Apoptosis / genetics Cell Line, Tumor DNA Damage / genetics Humans Neuroblastoma* / pathology Polycomb Repressive Complex 1 / genetics Polycomb Repressive Complex 1 / metabolism Polycomb-Group Proteins / genetics Tumor Suppressor Protein p53* / genetics Tumor Suppressor Protein p53* / metabolism
Human and Animal Cells NB69(RCB0480)