Synergistic activation of mutant TERT promoter by Sp1 and GABPA in BRAF V600E-driven human cancers
Synergistic activation of mutant TERT promoter by Sp1 and GABPA in BRAF V600E-driven human cancers
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DOI：
10.1038/s41698-020-00140-5
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
侯鹏
中科院分区：
文献类型：
--
作者：
吴永兴;史良;赵月磊;陈普;崔荣荣;祭美菊;何浓月;王茂德;李刚;侯鹏
The activating TERT promoter mutations and BRAFV600E mutation are well-established oncogenic alterations in human cancers..Coexistence of BRAFV600E and TERT promoter mutations is frequently found in multiple cancer types, and is strongly associated with.poor patient prognosis. Although the BRAFV600E-elicited activation of ERK has been demonstrated to contribute to TERT reactivation.by maintaining an active chromatin state, it still remains to be addressed how activated ERK is selectively recruited to mutant TERT.promoter. Here, we report that transcription factor GABPA mediates the regulation of BRAFV600E/MAPK signaling on TERT.reactivation by selectively recruiting activated ERK to mutant TERT promoter, where activated ERK can phosphorylate Sp1, thereby.resulting in HDAC1 dissociation and an active chromatin state. Meanwhile, phosphorylated Sp1 further enhances the binding of.GABPA to mutant TERT promoter. Taken together, our data indicate that GABPA and Sp1 synergistically activate mutant TERT.promoter, contributing to tumorigenesis and cancer progression, particularly in the BRAFV600E-driven human cancers. Thus, our.findings identify a direct mechanism that bridges two frequent oncogenic alterations together in TERT reactivation.
