Morgan Adams Foundation Pediatric Brain Tumor Research Program, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA.
Department of Biomedical Informatics, University of Colorado School of Medicine, Aurora, CO, USA.
Nat Commun. 2024 May 30;15(1):4616. doi: 10.1038/s41467-024-48214-3.
Dynamic regulation of gene expression is fundamental for cellular adaptation to exogenous stressors. P-TEFb-mediated pause-release of RNA polymerase II (Pol II) is a conserved regulatory mechanism for synchronous transcriptional induction in response to heat shock, but this pro-survival role has not been examined in the applied context of cancer therapy. Using model systems of pediatric high-grade glioma, we show that rapid genome-wide reorganization of active chromatin facilitates P-TEFb-mediated nascent transcriptional induction within hours of exposure to therapeutic ionizing radiation. Concurrent inhibition of P-TEFb disrupts this chromatin reorganization and blunts transcriptional induction, abrogating key adaptive programs such as DNA damage repair and cell cycle regulation. This combination demonstrates a potent, synergistic therapeutic potential agnostic of glioma subtype, leading to a marked induction of tumor cell apoptosis and prolongation of xenograft survival. These studies reveal a central role for P-TEFb underpinning the early adaptive response to radiotherapy, opening avenues for combinatorial treatment in these lethal malignancies.
基因表达的动态调控是细胞对外源应激适应的基础。P-TEFb 介导的 RNA 聚合酶 II（Pol II）暂停释放是一种保守的调节机制，可同步诱导热休克反应中的转录，但在癌症治疗的应用背景下，尚未对这种生存促进作用进行研究。我们使用小儿高级别神经胶质瘤的模型系统表明，快速的全基因组活性染色质重组促进了 P-TEFb 介导的新生转录诱导，这在暴露于治疗性电离辐射后的数小时内即可发生。同时抑制 P-TEFb 会破坏这种染色质重组，削弱转录诱导，从而消除关键的适应性程序，如 DNA 损伤修复和细胞周期调控。这种联合治疗具有强大的协同治疗潜力，与神经胶质瘤亚型无关，导致肿瘤细胞凋亡明显增加，并延长异种移植物的存活时间。这些研究揭示了 P-TEFb 在放疗早期适应性反应中的核心作用，为这些致命性恶性肿瘤的联合治疗开辟了途径。
