Polycomb group protein BMI1 protects neuroblastoma cells against DNA damage-induced apoptotic cell death
Polycomb group protein BMI1 protects neuroblastoma cells against DNA damage-induced apoptotic cell death
复制标题
DOI：
10.1016/j.yexcr.2022.113412
复制
发表时间：
2022-11-12
影响因子：
3.7
通讯作者：
Kamijo，Takehiko
中科院分区：
文献类型：
--
作者：
Akita，Nobuhiro;Okada，Ryu;Kamijo，Takehiko
多梳蛋白BMI 1的过度表达与癌症的发展和侵袭性相关。我们以前报道过MYCN诱导的BMI 1通过抑制NB细胞中肿瘤抑制因子的转录而正向调节NB细胞增殖。为了评估BMI 1作为NB治疗新靶点的潜力，我们检查了BMI 1减少对NB细胞的影响。NB细胞中的BMI 1敲低（KD）显著诱导其分化长达7天。BMI 1耗竭显著诱导NB细胞凋亡长达沿着14天，同时伴有p53的激活、p73的增加以及p53家族下游分子和途径的诱导，甚至在p53突变细胞中。体内BMI 1消耗显著抑制NB异种移植肿瘤生长。在NB细胞中，BMI 1减少激活ATM并增加γ-H2 AX。这些DNA损伤信号和凋亡性细胞死亡不能被多梳组分子EZH 2和RING 1B的转导所抵消。此外，EZH 2和RING 1B KD诱导NB细胞凋亡的程度与BMI 1 KD不同。总的来说，这些结果表明BMI 1作为NB分子治疗靶点的潜力，并首次证实了PcG蛋白在NB细胞DNA损伤反应中的共同作用。
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 inp53mutant cells. BMI1 depletionin vivomarkedly 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.