Histone Acetyltransferase KAT6A Upregulates PI3K/AKT Signaling through TRIM24 Binding.
Histone Acetyltransferase KAT6A Upregulates PI3K/AKT Signaling through TRIM24 Binding.
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组蛋白乙酰转移酶 KAT6A 通过 TRIM24 结合上调 PI3K/AKT 信号转导
DOI：
10.1158/0008-5472.can-17-1388
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发表时间：
2017-11-15
期刊：
影响因子：
11.2
通讯作者：
Feng H
中科院分区：
文献类型：
--
作者：
Lv D;Jia F;Hou Y;Sang Y;Alvarez AA;Zhang W;Gao WQ;Hu B;Cheng SY;Ge J;Li Y;Feng H
赖氨酸乙酰转移酶KAT6A是一种染色质调节剂，有助于组蛋白修饰和癌症，但其作用的基础尚不清楚。在这里，我们发现KAT6A信号通路促进胶质母细胞瘤（GBM），在那里它被上调。KAT6A表达与GBM患者生存率相关。在原位小鼠异种移植模型系统中，KAT6A沉默抑制细胞增殖、细胞迁移、集落形成和肿瘤发展。机制研究表明，KAT6A乙酰化组蛋白H3的赖氨酸23 (H3K23)，招募核受体结合蛋白TRIM24激活PIK3CA转录，从而增强PI3K/AKT信号传导和肿瘤发生。过表达活化的AKT或PIK3CA可挽救由于KAT6A沉默而导致的生长抑制。相反，pan-PI3K抑制剂LY294002则消除了KAT6A的促生长作用。过度表达KAT6A或TRIM24，而不表达KAT6A乙酰转移酶活性缺陷突变体或缺乏h3k23ac结合位点的TRIM24突变体，可促进PIK3CA表达、AKT磷酸化和细胞增殖。综上所述，我们的研究结果确定了KAT6A在胶质瘤形成中的重要作用，使其成为GBM治疗的候选治疗靶点。癌症Res;77 (22);6190 - 201。AACR©2017。
Lysine acetyltransferase KAT6A is a chromatin regulator that contributes to histone modification and cancer, but the basis of its actions are not well understood. Here, we identify a KAT6A signaling pathway that facilitates glioblastoma (GBM), where it is upregulated. KAT6A expression was associated with GBM patient survival. KAT6A silencing suppressed cell proliferation, cell migration, colony formation, and tumor development in an orthotopic mouse xenograft model system. Mechanistic investigations demonstrated that KAT6A acetylates lysine 23 of histone H3 (H3K23), which recruits the nuclear receptor binding protein TRIM24 to activate PIK3CA transcription, thereby enhancing PI3K/AKT signaling and tumorigenesis. Overexpressing activated AKT or PIK3CA rescued the growth inhibition due to KAT6A silencing. Conversely, the pan-PI3K inhibitor LY294002 abrogated the growth-promoting effect of KAT6A. Overexpression of KAT6A or TRIM24, but not KAT6A acetyltransferase activity-deficient mutants or TRIM24 mutants lacking H3K23ac-binding sites, promoted PIK3CA expression, AKT phosphorylation, and cell proliferation. Taken together, our results define an essential role of KAT6A in glioma formation, rationalizing its candidacy as a therapeutic target for GBM treatment. Cancer Res; 77(22); 6190-201. ©2017 AACR.