Argininosuccinate lyase drives activation of mutant TERT promoter in glioblastomas
Argininosuccinate lyase drives activation of mutant TERT promoter in glioblastomas
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精氨基琥珀酸裂合酶驱动胶质母细胞瘤中突变TERT启动子的激活
DOI：
10.1016/j.molcel.2022.09.024
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发表时间：
2022
期刊：
影响因子：
16
通讯作者：
Xu Qian
中科院分区：
文献类型：
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作者：
Zhumei Shi;Xin Ge;Mengdie Li;Jianxing Yin;Xiefeng Wang;Junxia Zhang;Dongyin Chen;Xinjiang Li;Xiuxing Wang;Jing Ji;Yongping You;Xu Qian
癌症特异性tert启动子突变通过为e - 26转录因子，特别是GABPA创造新的结合基序，与表观遗传沉默的tertgene的再激活有关。这些突变是如何将tert从表观遗传抑制状态切换到表达状态的尚未明确。在这里，我们发现EGFR激活诱导erk1 /2依赖性精氨酸琥珀酸裂解酶（ASL） Ser417位点的磷酸化，导致ASL和GABPA在tert启动子的突变区域相互作用。asl产生的富马酸抑制KDM5C，导致组蛋白H3 Lys4 （H3K4me3）的三甲基化增强，这反过来促进c-Myc totertpromoter募集TERT表达。ASL S417A的表达可以消除其与GABPA的结合，从而降低TERT的表达，抑制端粒酶活性，缩短端粒长度，损害小鼠脑肿瘤的生长。这项研究揭示了突变tert启动子表观遗传激活的未被认识的机制，其中gabpa相互作用的ASL起重要作用。
Cancer-specificTERTpromoter mutations have been linked to the reactivation of epigenetically silencedTERTgene by creatingde novobinding motifs for E-Twenty-Six transcription factors, especially GABPA. How these mutations switch onTERTfrom epigenetically repressed states to expressed states have not been defined. Here, we revealed that EGFR activation induces ERK1/2-dependent phosphorylation of argininosuccinate lyase (ASL) at Ser417 (S417), leading to interactions between ASL and GABPA at the mutant regions ofTERTpromoters. The ASL-generated fumarate inhibits KDM5C, leading to enhanced trimethylation of histone H3 Lys4 (H3K4me3), which in turn promotes the recruitment of c-Myc toTERTpromoters for TERT expression. Expression of ASL S417A, which abrogates its binding with GABPA, results in reduced TERT expression, inhibited telomerase activity, shortened telomere length, and impaired brain tumor growth in mice. This study reveals an unrecognized mechanistic insight into epigenetically activation of mutantTERTpromoters where GABPA-interacted ASL plays an instrumental role.