在癌细胞静止中NuRD复合体和改变蛋白质稳定性的作用
Qi Jiang1,2, Michelle Ertel3, Austin Arrigo1
1Obstetrics and Gynecology Magee-Womens Research Inst. & Foundation, Pittsburgh, PA, USA.
bioRxiv : the preprint server for biology
|February 24, 2025
概括
静止,细胞周期的退出状态,驱动卵巢癌 (OvCa) 的化学抵抗. 用HDAC抑制剂向NuRD复合体可以诱导静止,并使OvCa细胞对组合疗法敏感.
科学领域:
- 在瘤学瘤学.
- 细胞生物学 细胞生物学
- 分子生物学分子生物学
背景情况:
- 细胞毒性化疗是卵巢癌 (OvCa) 的标准治疗方法,但化学抵抗导致患者的治疗结果不佳.
- 化学抵抗机制对于理解至关重要,细胞静止是一个尚未探索的因素.
- 静止细胞退出细胞周期,并且对针对快速分裂细胞的疗法具有抗性.
研究的目的:
- 调查核细胞重塑和脱乙酶 (NuRD) 复合体在卵巢癌细胞静止中的作用.
- 通过了解卵巢癌中化学抵抗的分子基础来确定新的治疗策略.
主要方法:
- 在静止的OvCa细胞 (qOvCa) 中分析了CHD4和MBD3,NuRD复杂组件的下调.
- 使用CHD4/MBD3倒置和基因素脱乙酶抑制剂 (HDACi),如沃里诺斯塔特,以诱导OvCa细胞的静止.
- 进行RNA测序 (RNA-Seq) 来确认与静止相关的基因表达变化.
- 在qOvCa和HDACi处理的细胞中评估了蛋白质稳定性改变 (蛋白质酶活性,自).
- 评估了涉及HDACi与蛋白酶体或自抑制剂的组合疗法.
- 通过将OvCa静止特征与酵母静止基因进行比较,确定了一种保存的"静止细胞核心特征".
主要成果:
- 在静止的OvCa细胞中,CHD4和MBD3的下调.
- 对CHD4/MBD3的抑制或对HDACi (vorinostat) 的治疗成功诱导了OvCa细胞的静止状态.
- RNA-Seq证实,HDACi治疗诱导了与静止相一致的基因表达变化.
- 静止的OvCa细胞表现出改变的蛋白质稳定,包括增加的蛋白质酶活性和自.
- 使用HDACi与蛋白酶体或自抑制剂的联合治疗导致了协同作用的癌细胞死亡.
- 在不同癌症类型中发现了一种保存的"静止细胞核心签名".
结论:
- NuRD复杂降低调节与诱导卵巢癌细胞静止有关.
- HDAC 抑制剂可以诱导静止,并使卵巢癌细胞对向蛋白质稳定性的组合疗法敏感.
- 鉴定到的"静止细胞核心签名"表明,对多种癌症类型的治疗标可以保留.
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