靶向 SWI/SNF ATPases 可降低神经母细胞瘤细胞的可塑性。

IF 9.4 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY EMBO Journal Pub Date : 2024-10-01 Epub Date: 2024-08-22 DOI:10.1038/s44318-024-00206-1
Man Xu, Jason J Hong, Xiyuan Zhang, Ming Sun, Xingyu Liu, Jeeyoun Kang, Hannah Stack, Wendy Fang, Haiyan Lei, Xavier Lacoste, Reona Okada, Raina Jung, Rosa Nguyen, Jack F Shern, Carol J Thiele, Zhihui Liu
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引用次数: 0

摘要

肿瘤细胞的异质性决定了神经母细胞瘤(NB)的治疗反应性,这是一种源自神经嵴细胞的癌症。神经母细胞瘤包括两种主要亚型:肾上腺素能型和间质型。肾上腺素能特性在 NB 肿瘤中占主导地位,而间质特性则在化疗后或复发后变得丰富。这些亚型之间的相互转换有助于NB血统的可塑性,但驱动这种表型转换的潜在机制仍不清楚。在这里,我们证明了SWI/SNF染色质重塑复合体ATP酶在肾上腺素能型NB中建立间质基因允许的染色质状态、促进谱系可塑性方面的重要作用。用SMARCA2/4双降解器靶向SWI/SNF ATP酶可有效抑制NB细胞的增殖、侵袭,尤其是细胞的可塑性,从而防止化疗耐药。从机理上讲,耗尽SWI/SNF ATP酶会压缩顺式调节元件,降低增强子活性,并从DNA中移除核心转录因子(MYCN、HAND2、PHOX2B和GATA3),从而抑制与可塑性相关的转录程序。这些发现强调了SWI/SNF ATP酶在驱动神经母细胞瘤内在可塑性和耐药性方面的关键作用,突出了该癌症综合治疗的表观遗传学靶点。
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Targeting SWI/SNF ATPases reduces neuroblastoma cell plasticity.

Tumor cell heterogeneity defines therapy responsiveness in neuroblastoma (NB), a cancer derived from neural crest cells. NB consists of two primary subtypes: adrenergic and mesenchymal. Adrenergic traits predominate in NB tumors, while mesenchymal features becomes enriched post-chemotherapy or after relapse. The interconversion between these subtypes contributes to NB lineage plasticity, but the underlying mechanisms driving this phenotypic switching remain unclear. Here, we demonstrate that SWI/SNF chromatin remodeling complex ATPases are essential in establishing an mesenchymal gene-permissive chromatin state in adrenergic-type NB, facilitating lineage plasticity. Targeting SWI/SNF ATPases with SMARCA2/4 dual degraders effectively inhibits NB cell proliferation, invasion, and notably, cellular plasticity, thereby preventing chemotherapy resistance. Mechanistically, depletion of SWI/SNF ATPases compacts cis-regulatory elements, diminishes enhancer activity, and displaces core transcription factors (MYCN, HAND2, PHOX2B, and GATA3) from DNA, thereby suppressing transcriptional programs associated with plasticity. These findings underscore the pivotal role of SWI/SNF ATPases in driving intrinsic plasticity and therapy resistance in neuroblastoma, highlighting an epigenetic target for combinational treatments in this cancer.

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来源期刊
EMBO Journal
EMBO Journal 生物-生化与分子生物学
CiteScore
18.90
自引率
0.90%
发文量
246
审稿时长
1.5 months
期刊介绍: The EMBO Journal has stood as EMBO's flagship publication since its inception in 1982. Renowned for its international reputation in quality and originality, the journal spans all facets of molecular biology. It serves as a platform for papers elucidating original research of broad general interest in molecular and cell biology, with a distinct focus on molecular mechanisms and physiological relevance. With a commitment to promoting articles reporting novel findings of broad biological significance, The EMBO Journal stands as a key contributor to advancing the field of molecular biology.
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