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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Sp1 和 GABPA 在 BRAF V600E 驱动的人类癌症中协同激活突变 TERT 启动子
DOI：
10.1038/s41698-020-00140-5
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发表时间：
2021-01-22
影响因子：
7.9
通讯作者：
Hou P
中科院分区：
文献类型：
--
作者：
Wu Y;Shi L;Zhao Y;Chen P;Cui R;Ji M;He N;Wang M;Li G;Hou P
激活TERT启动子突变和BRAFV600E突变是人类癌症中公认的致癌改变。BRAFV600E和TERT启动子突变的共存在多种癌症类型中经常发现，并且与患者预后不良密切相关。尽管brafv600e引发的ERK激活已被证明通过维持活跃的染色质状态来促进TERT的再激活，但活化的ERK如何被选择性地招募到突变TERT启动子仍有待解决。在这里，我们报道了转录因子GABPA通过选择性地将活化的ERK招募到突变TERT启动子，介导BRAFV600E/MAPK信号通路对TERT再激活的调节，其中活化的ERK可以磷酸化Sp1，从而导致HDAC1解离和活性染色质状态。同时，Sp1磷酸化进一步增强了GABPA与突变体TERT启动子的结合。综上所述，我们的数据表明，GABPA和Sp1协同激活突变TERT启动子，促进肿瘤发生和癌症进展，特别是在brafv600e驱动的人类癌症中。因此，我们的发现确定了在TERT再激活中连接两种常见致癌改变的直接机制。
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.
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影响因子：
4.8
作者：
Chinenov, Y;Henzl, M;Martin, ME
通讯作者：
Martin, ME
31种癌症类型的端粒长度和躯体改变的系统分析。
影响因子：
30.8
作者：
Barthel FP;Wei W;Tang M;Martinez-Ledesma E;Hu X;Amin SB;Akdemir KC;Seth S;Song X;Wang Q;Lichtenberg T;Hu J;Zhang J;Zheng S;Verhaak RG
通讯作者：
Verhaak RG
DOI：
10.1126/science.1229259
发表时间：
2013-02-22
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Huang FW;Hodis E;Xu MJ;Kryukov GV;Chin L;Garraway LA
通讯作者：
Garraway LA
影响因子：
56.9
作者：
Batchelor, AH;Piper, DE;Wolberger, C
通讯作者：
Wolberger, C
基因组和生化洞察ETS转录因子的特异性。
影响因子：
16.6
作者：
Hollenhorst PC;McIntosh LP;Graves BJ
通讯作者：
Graves BJ