Laboratory for Cellular and Molecular Thyroid Research, Division of Endocrinology, Diabetes, and Metabolism, The Johns Hopkins University School of Medicine, Baltimore, MD 21287.
Laboratory for Cellular and Molecular Thyroid Research, Division of Endocrinology, Diabetes, and Metabolism, The Johns Hopkins University School of Medicine, Baltimore, MD 21287
Proc Natl Acad Sci U S A. 2021 Mar 16;118(11). doi: 10.1073/pnas.2022779118.
The telomerase reverse transcriptase (TERT) has long been pursued as a direct therapeutic target in human cancer, which is currently hindered by the lack of effective specific inhibitors of TERT. The FOS/GABPB/(mutant) cascade plays a critical role in the regulation of mutant , in which FOS acts as a transcriptional factor for to up-regulate the expression of GABPB, which in turn activates mutant but not wild-type promoter, driving TERT-promoted oncogenesis. In the present study, we demonstrated that inhibiting this cascade by targeting FOS using FOS inhibitor T-5224 suppressed mutant cancer cells and tumors by inducing robust cell apoptosis; these did not occur in wild-type cells and tumors. Mechanistically, among 35 apoptotic cascade-related proteins tested, the apoptosis induced in this process specifically involved the transcriptional activation of tumor necrosis factor-related apoptosis-inducing ligand receptor 2 () and inactivation of two key players in the apoptotic cascade, which normally initiate and suppress the apoptotic cascade, respectively. These findings with suppression of FOS were reproduced by direct knockdown of TERT and prevented by prior knockdown of TRAIL-R2. Further experiments demonstrated that TERT acted as a direct transcriptional factor of up-regulating its expression. Thus, this study identifies a therapeutic strategy for promoter mutation-driven cancers by targeting FOS in the FOS/GABPB/(mutant) cascade, circumventing the current challenge in pharmacologically directly targeting TERT itself. This study also uncovers a mechanism through which TERT controls cell apoptosis by transcriptionally regulating two key players in the apoptotic cascade.
端粒酶逆转录酶 (TERT) 长期以来一直被视为人类癌症的直接治疗靶点，但目前缺乏有效的 TERT 特异性抑制剂，这一目标受到了阻碍。FOS/GABPB/(突变型)级联在调节突变型中起着关键作用，其中 FOS 作为转录因子，上调 GABPB 的表达，GABPB 反过来又激活突变型但不激活野生型 TERT 启动子，驱动 TERT 促进肿瘤发生。在本研究中，我们通过使用 FOS 抑制剂 T-5224 靶向 FOS 来抑制这个级联反应，发现其通过诱导强烈的细胞凋亡来抑制突变型癌症细胞和肿瘤，而野生型 TERT 细胞和肿瘤则不会发生这种情况。从机制上讲，在测试的 35 种凋亡级联相关蛋白中，该过程诱导的凋亡特别涉及肿瘤坏死因子相关凋亡诱导配体受体 2 () 的转录激活和凋亡级联中的两个关键蛋白的失活，这两个蛋白分别是凋亡级联的起始和抑制因子。抑制 FOS 可以重现这些发现，并且可以通过预先敲低 TRAIL-R2 来阻止。进一步的实验表明，TERT 作为一个直接的转录因子，上调 的表达。因此，本研究通过靶向 FOS/GABPB/(突变型)级联中的 FOS，为针对 FOS 抑制的 启动子突变驱动的癌症提供了一种治疗策略，规避了目前在药理学上直接靶向 TERT 本身的挑战。本研究还揭示了 TERT 通过转录调控凋亡级联中的两个关键蛋白来控制细胞凋亡的机制。
