缺少CDK12诱导BRD4S通过增强相分离和染色体参与来促进癌症转移
Hao Li1, Jindan Luo1, Huaiyuan Liang2
1First Affiliated Hospital Zhejiang University, Hangzhou, Zhejiang, China.
Cancer research
|November 25, 2025
概括
CDK12 缺乏导致癌症转移,通过通过内部多基解来增加BRD4 简体形式 (BRD4S). BRD4S通过激活TGF-β信号来驱动癌细胞的扩散,为CDK12缺乏癌症提供治疗点.
科学领域:
- 分子瘤学分子瘤学
- 癌症生物学 癌症生物学
- 基因规则 基因规则
背景情况:
- CDK12 (循环素依赖性激酶 12) 失活与人类的侵袭性癌症和转移有关.
- 通过CDK12损失促进癌症进展的确切机制仍然不完全理解.
研究的目的:
- 为了阐明CDK12缺乏在癌症中的功能后果.
- 为了确定调解CDK12突变癌症转移的分子途径.
- 探索CDK12缺乏癌症的潜在治疗点.
主要方法:
- 利用CUT&Tag和RNA测序来分析基因表达和蛋白质结合.
- 研究了BRD4异型的蛋白质-蛋白质相互作用和相分离特性.
- 采用了体外细胞扩散试验和体内转移模型.
主要成果:
- 缺乏CDK12会诱导BRD4的内基多化 (IPA),导致BRD4简体形式 (BRD4S) 的表达增加.
- 由于缺乏内在无序区域 (IDR),BRD4S通过其基相互作用结构域 (BID) 展现了增强的相分离.
- BRD4S优先结合TGF-β信号基因 (例如,TGFB2,LTBP1) 的促进者,驱动它们的表达并促进癌细胞的扩散和转移.
- BET或TGF-β通路抑制剂有效地阻断了BRD4S介导的转移.
结论:
- 通过IPA,CDK12损失触发了BRD4S的产生,这是一种驱动癌症转移的新机制.
- 通过BRD4S介导的TGF-β信号的激活是CDK12缺乏癌症转移的关键驱动因素.
- 向BRD4S或TGF-β通路对于缺乏CDK12的恶性瘤是一种有前途的治疗策略.
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