Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720.
Department of Neurological Surgery, University of California, San Francisco, CA 94158.
Proc Natl Acad Sci U S A. 2021 Mar 30;118(13). doi: 10.1073/pnas.2008772118.
Most glioblastomas (GBMs) achieve cellular immortality by acquiring a mutation in the telomerase reverse transcriptase () promoter. promoter mutations create a binding site for a GA binding protein (GABP) transcription factor complex, whose assembly at the promoter is associated with reactivation and telomere maintenance. Here, we demonstrate increased binding of a specific GABPB1L-isoform-containing complex to the mutant promoter. Furthermore, we find that promoter mutant GBM cells, unlike wild-type cells, exhibit a critical near-term dependence on GABPB1L for proliferation, notably also posttumor establishment in vivo. Up-regulation of the protein paralogue GABPB2, which is normally expressed at very low levels, can rescue this dependence. More importantly, when combined with frontline temozolomide (TMZ) chemotherapy, inducible GABPB1L knockdown and the associated reduction led to an impaired DNA damage response that resulted in profoundly reduced growth of intracranial GBM tumors. Together, these findings provide insights into the mechanism of cancer-specific regulation, uncover rapid effects of GABPB1L-mediated suppression in GBM maintenance, and establish GABPB1L inhibition in combination with chemotherapy as a therapeutic strategy for promoter mutant GBM.
大多数胶质母细胞瘤（GBM）通过在端粒酶逆转录酶（）启动子中获得突变来实现细胞永生。启动子突变创造了一个与 GA 结合蛋白（GABP）转录因子复合物结合的位点，该复合物在启动子上的组装与重新激活和端粒维持有关。在这里，我们证明了特定的 GABPB1L 同种型包含复合物与突变的结合增加。此外，我们发现与野生型细胞不同，突变的 GBM 细胞表现出对 GABPB1L 的关键短期增殖依赖性，尤其是在体内肿瘤建立后也是如此。通常低水平表达的蛋白同源物 GABPB2 的上调可以挽救这种依赖性。更重要的是，当与一线替莫唑胺（TMZ）化疗联合使用时，诱导型 GABPB1L 敲低及其相关的减少导致 DNA 损伤反应受损，导致颅内 GBM 肿瘤的生长明显减少。总之，这些发现深入了解了癌症特异性调控的机制，揭示了 GABPB1L 介导的在 GBM 维持中的快速作用，并确立了与化疗联合使用 GABPB1L 抑制作为突变的 GBM 的治疗策略。
