多种恶性肿瘤中均证实存在高频率的TERT启动子突变，该突变可产生新的ETS转录因子结合位点（如GABPA），进而上调TERT的表达、促进肿瘤的进展。尽管先前已有研究证实，GABPA可介导长距离的染色体相互作用，激活TERT表达，但仍有许多机制尚不明确。我们前期的研究发现，GABPA在胶质瘤患者中表达上调，敲减GABPA可显著降低肿瘤细胞的增殖能力。此外，我们还证实GABPA可介导磷酸化的ERK特异性结合到TERT启动子区，并磷酸化Sp1，进而引起染色质重塑；同时，磷酸化Sp1进一步促进GABPA在TERT启动子区富集。本项目拟在前期工作的基础上，深入研究TERT启动子突变通过引起染色质重塑，上调TERT表达的分子机制，并利用CADD（computer aided drug design）技术在小分子库中筛选针对TERT启动子突变的小分子化合物，为携带该突变的肿瘤提供新的治疗策略。

Two cancer-specific somatic mutations (C228T and C250T) in the TERT promoter(TERTp) have been found in different types of cancer such as melanoma, glioblastoma, hepatocellular carcinoma, urothelial bladder carcinoma and thyroid carcinoma. These mutations can upregulate TERT expression through creatinga novel ETS transcription factor binding motif (such as GABPA), contributing to tumorigenesis. Although a previous study has reported that these mutations reactivate TERT expression through long-range chromatin interactions via transcription factor GABPA, the molecular mechanisms remain largely unclear.Our preliminary datashowed thatGABPA was significantly upregulated in glioma tissues compared to normal brain tissues. Knocking down GABPA expression in TERTp mutated cell linessignificantly inhibited cell proliferation. In addition, we also demonstrated thatGABPA recruited phosphorylated ERK onto TERTp to promoteSp1 phosphorylation, thereby resulting in enrichment of active histone marks on these promoters. Subsequently, phosphorylated Sp1 further recruitedGABPAonto TERTp. Based on these findings, in this project, we attempt to explore the molecular mechanism underlying TERT activation through chromatin remodeling via TERTp mutations, and screen small molecular inhibitors specifically targeting TERTp mutations through CADD (computer aided drug design) strategy. Our findings will provide a potential therapeutic strategy for tumors carrying these mutations.