Wu Yongxing, Shi Liang, Zhao Yuelei, Chen Pu, Cui Rongrong, Ji Meiju, He Nongyue, Wang Maode, Li Gang, Hou Peng
Key Laboratory for Tumor Precision Medicine of Shaanxi Province and Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, 710061, Xi'an, People's Republic of China.
Department of Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, 710061, Xi'an, People's Republic of China.
NPJ Precis Oncol. 2021 Jan 22;5(1):3. doi: 10.1038/s41698-020-00140-5.
The activating TERT promoter mutations and BRAF mutation are well-established oncogenic alterations in human cancers. Coexistence of BRAF and TERT promoter mutations is frequently found in multiple cancer types, and is strongly associated with poor patient prognosis. Although the BRAF-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 BRAF/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 BRAF-driven human cancers. Thus, our findings identify a direct mechanism that bridges two frequent oncogenic alterations together in TERT reactivation.
激活型端粒酶逆转录酶（TERT）启动子突变和BRAF突变是人类癌症中公认的致癌性改变。BRAF和TERT启动子突变共存常见于多种癌症类型，且与患者预后不良密切相关。尽管已证明BRAF引发的细胞外信号调节激酶（ERK）激活通过维持活跃的染色质状态促进TERT重新激活，但激活的ERK如何被选择性招募到突变的TERT启动子仍有待解决。在此，我们报告转录因子GABPA通过将激活的ERK选择性招募到突变的TERT启动子来介导BRAF/丝裂原活化蛋白激酶（MAPK）信号对TERT重新激活的调控，激活的ERK可在此磷酸化Sp1，从而导致组蛋白去乙酰化酶1（HDAC1）解离并形成活跃的染色质状态。同时，磷酸化的Sp1进一步增强GABPA与突变TERT启动子的结合。综上所述，我们的数据表明GABPA和Sp1协同激活突变的TERT启动子，促进肿瘤发生和癌症进展，尤其是在BRAF驱动的人类癌症中。因此，我们的研究结果确定了一种在TERT重新激活过程中将两种常见致癌性改变联系在一起的直接机制。
