Walker Faye M, Sobral Lays Martin, Danis Etienne, Sanford Bridget, Balakrishnan Ilango, Wang Dong, Pierce Angela, Karam Sana D, Serkova Natalie J, Foreman Nicholas K, Venkataraman Sujatha, Dowell Robin, Vibhakar Rajeev, Dahl Nathan A
bioRxiv. 2023 Jan 25:2023.01.24.525424. doi: 10.1101/2023.01.24.525424.
Dynamic regulation of gene expression is fundamental for cellular adaptation to exogenous stressors. PTEFb-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 PTEFb-mediated nascent transcriptional induction within hours of exposure to therapeutic ionizing radiation. Concurrent inhibition of PTEFb 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 PTEFb underpinning the early adaptive response to radiotherapy, opening new avenues for combinatorial treatment in these lethal malignancies.
基因表达的动态调控是细胞适应外源性应激源的基础。P-TEFb介导的RNA聚合酶II（Pol II）暂停释放是一种保守的调控机制，用于响应热休克进行同步转录诱导，但这种促生存作用尚未在癌症治疗的应用背景中进行研究。使用小儿高级别胶质瘤模型系统，我们发现活性染色质在全基因组范围内的快速重组有助于在暴露于治疗性电离辐射数小时内实现P-TEFb介导的新生转录诱导。同时抑制P-TEFb会破坏这种染色质重组并削弱转录诱导，从而废除诸如DNA损伤修复和细胞周期调控等关键适应性程序。这种联合疗法显示出一种强大的、与胶质瘤亚型无关的协同治疗潜力，导致肿瘤细胞凋亡显著诱导并延长异种移植生存期。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，为这些致命恶性肿瘤的联合治疗开辟了新途径。
