气候变化领域集成服务门户(CCPortal): Therapeutic targeting of FOS in mutant TERT cancers through removing TERT suppression of apoptosis via regulating survivin and TRAIL-R2

CCPortal

DOI	10.1073/pnas.2022779118
	Therapeutic targeting of FOS in mutant TERT cancers through removing TERT suppression of apoptosis via regulating survivin and TRAIL-R2
	Liu R.; Tan J.; Shen X.; Jiang K.; Wang C.; Zhu G.; Xing M.
发表日期	2021
ISSN	00278424
卷号	118 期号:11
英文摘要	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) TERT cascade plays a critical role in the regulation of mutant TERT, in which FOS acts as a transcriptional factor for GABPB to up-regulate the expression of GABPB, which in turn activates mutant but not wild-type TERT 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 TERT cancer cells and tumors by inducing robust cell apoptosis; these did not occur in wild-type TERT 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 (TRAIL-R2) and inactivation of survivin, 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 survivin, upregulating its expression. Thus, this study identifies a therapeutic strategy for TERT promoter mutation-driven cancers by targeting FOS in the FOS/GABPB/(mutant) TERT 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. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Apoptosis; FOS; Survivin; TERT promoter mutation; TRAIL-R2
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180262
作者单位	Laboratory for Cellular and Molecular Thyroid Research, Division of Endocrinology, Diabetes, and Metabolism, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States
推荐引用方式 GB/T 7714	Liu R.,Tan J.,Shen X.,et al. Therapeutic targeting of FOS in mutant TERT cancers through removing TERT suppression of apoptosis via regulating survivin and TRAIL-R2[J],2021,118(11).
APA	Liu R..,Tan J..,Shen X..,Jiang K..,Wang C..,...&Xing M..(2021).Therapeutic targeting of FOS in mutant TERT cancers through removing TERT suppression of apoptosis via regulating survivin and TRAIL-R2.Proceedings of the National Academy of Sciences of the United States of America,118(11).
MLA	Liu R.,et al."Therapeutic targeting of FOS in mutant TERT cancers through removing TERT suppression of apoptosis via regulating survivin and TRAIL-R2".Proceedings of the National Academy of Sciences of the United States of America 118.11(2021).