昼夜调节器REV-ERBα的功能逆转导致瘤基因基因重编程
Yatian Yang1, Xiong Zhang1, Demin Cai1
1Department of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, Sacramento, CA 95817.
概括
循环节律 (CR) 调节器REV-ERBα在癌症中切换功能,成为推动瘤生长的强有力的激活剂. 用SR8278和BRD4抑制剂准这种开关可以有效地抑制癌症的进展.
科学领域:
- 分子生物学分子生物学
- 癌症研究 癌症研究
- 时间生物学 时间生物学
背景情况:
- 昼夜节律 (CR) 的失调与癌症有关,但潜在的机制尚不清楚.
- REV-ERBα是一种关键的CR调节剂,与细胞平衡和疾病有关.
- 了解REV-ERBα在瘤发生中的作用对于开发新的癌症疗法至关重要.
研究的目的:
- 为了研究REV-ERBα在癌症中的功能性改变.
- 阐明REV-ERBα驱动瘤发生的分子机制.
- 评估针对REV-ERBα在癌症治疗中的治疗潜力.
主要方法:
- 在瘤样本中分析REV-ERBα基因组结合和功能模式.
- 研究REV-ERBα的蛋白质复合体关联 (NCoR/HDAC3与BRD4/p300).
- 在临床前癌症模型中药理上抑制REV-ERBα (SR8278) 和BRD4.
主要成果:
- REV-ERBα在癌症中经历了功能逆转,从抑制剂转变为强大的激活剂.
- 激活的REV-ERBα直接上调数千个基因,包括瘤信号通路 (MAPK,PI3K-Akt).
- 对REV-ERBα和BRD4的联合向协同抑制瘤生长和瘤致癌程序.
结论:
- REV-ERBα的功能开关是癌症发展的新范式,重编程基因表达向瘤产生.
- 针对REV-ERBα功能逆转是一种有前途的治疗策略,用于各种癌症.
- 涉及SR8278和BRD4抑制剂的联合治疗显示出显著的抗瘤疗效.
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