通过CBP/p300抑制对默克尔细胞癌的药理学逆转
Joseph L Collura1, Kuan Cheok Lei2,3, Mitalee Chandra2
1Cancer Virology Program, University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA 15213.
概括
针对CREB结合蛋白 (CBP) /p300的小分子通过抑制病毒coprotein表达来抑制默克尔细胞癌 (MCC). 这会诱导细胞循环停止并促进神经元分化,为MCC提供一种新的治疗策略.
科学领域:
- 在瘤学瘤学.
- 病毒学 病毒学
- 细胞生物学 细胞生物学
背景情况:
- 默克尔细胞多瘤病毒 (MCV) T抗原通过瘤信号驱动默克尔细胞癌 (MCC).
- 病毒T抗原的表达取决于细胞联合激活剂CREB结合蛋白 (CBP) /p300.
研究的目的:
- 研究抑制MCC中CBP/p300的治疗潜力.
- 阐明MCC细胞转化和分化背后的机制.
主要方法:
- 用CBP/p300的小分子抑制剂对MCC细胞进行治疗.
- RNA测序以分析基因表达变化.
- 分析一种罕见的MCC病例,细胞组成混合.
主要成果:
- 抑制CBP/p300抑制T抗原表达,诱导细胞循环停止,并促进神经元分化.
- 观察到E2F,Myc和mTORC1瘤性通路的下调.
- 一个罕见的MCC病例的转录形状反映了受抑制剂治疗的细胞,表明分化有助于瘤异质性.
结论:
- 准CBP/p300提供了一种策略,可以逆转MCC细胞转化并诱导分化.
- 在MCC中瘤异质性可能部分是由分化过程驱动的.
- 建立了癌症转化和分化状态之间可逆切换的模型系统.
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